(Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors

ABSTRACT

The invention relates to (hetero)aryl cyclopropylamine compounds, including particularly the compounds of formula (I) as described and defined herein, and their use in therapy, including, e.g., in the treatment or prevention of cancer, a neurological disease or condition, or a viral infection.

The invention relates to (hetero)aryl cyclopropylamine compounds,particularly compounds of formula I, Ia, Ia-1, Ib and Ic, moreparticularly compounds of formula I and Ia, as described and definedherein, and their use in therapy, including e.g., in the treatment orprevention of cancer, a neurological disease, or a viral infection.

Aberrant gene expression in affected tissue as compared to normal tissueis a common characteristic of many human diseases. This is true forcancer and many neurological diseases which are characterized by changesin gene expression patterns. Gene expression patterns are controlled atmultiple levels in the cell. Control of gene expression can occurthrough modifications of DNA: DNA promoter methylation is associatedwith suppression of gene expression. Several inhibitors of DNAmethylation are approved for clinical use including the blockbusterVidaza™. Another class of modifications involve histones which form theprotein scaffold that DNA is normally associated with (coiled around) ineukaryotic cells. Histones play a crucial role in organizing DNA and theregulated coiling and uncoiling of DNA around the histones is criticalin controlling gene expression—coiled DNA is typically not accessiblefor gene transcription. A number of histone modifications have beendiscovered including histone acetylation, histone lysine methylation,histone arginine methylation, histone ubiquinylation, and histonesumoylation, many of which modify accessibility to the associated DNA bythe cells transcriptional machinery. These histone marks serve torecruit various protein complexes involved in transcription andrepression. An increasing number of studies are painting an intricatepicture of how various combinations of histone marks control geneexpression in cell-type specific manner and a new term has been coinedto capture this concept: the histone code.

The prototypical histone mark is histone acetylation. Histone acetyltransferase and histone deacetylases are the catalytic machines involvedin modulation of this histone mark although typically these enzymes areparts of multiprotein complexes containing other proteins involved inreading and modifying histone marks. The components of these proteincomplexes are typically cell-type specific and typically comprisetranscriptional regulators, repressors, co-repressors, receptorsassociated with gene expression modulation (e.g., estrogen or androgenreceptor). Histone deacetylase inhibitors alter the histone acetylationprofile of chromatin. Accordingly, histone deacetylase inhibitors likeVorinostat (SAHA), Trichostatin A (TSA), and many others have been shownto alter gene expression in various in vitro and in vivo animal models.Clinically, histone deacetylase inhibitors have demonstrated activity inthe cancer setting and are being investigated for oncology indicationsas well as for neurological conditions and other diseases.

Another modification that is involved in regulating gene expression ishistone methylation including lysine and arginine methylation. Themethylation status of histone lysines has recently been shown to beimportant in dynamically regulating gene expression.

A group of enzymes known as histone lysine methyl transferases andhistone lysine demethylases are involved in histone lysinemodifications. One particular human histone lysine demethylase enzymecalled Lysine Specific Demethylase-1 (LSD1) was recently discovered (Shiet al. (2004) Cell 119:941) to be involved in this crucial histonemodification. LSD1 has a fair degree of structural similarity, and aminoacid identity/homology to polyamine oxidases and monoamine oxidases, allof which (i.e., MAO-A, MAO-B and LSD1) are flavin dependent amineoxidases which catalyze the oxidation of nitrogen-hydrogen bonds and/ornitrogen carbon bonds. LSD1 has been recognized as an interesting targetfor the development of new drugs to treat cancer, neurological diseasesand other conditions.

Cyclopropylamine containing compounds are known to inhibit a number ofmedically important targets including amine oxidases like MonoamineOxidase A (MAO-A; or MAOA), Monoamine Oxidase B (MAO-B; or MAOB), andLysine Specific Demethylase-1 (LSD1). Tranylcypromine (also known as2-phenylcyclopropylamine), which is the active ingredient of Parnate®and one of the best known examples of a cyclopropylamine, is known toinhibit all of these enzymes. Since MAO-A inhibition may cause undesiredside effects, it would be desirable to identify cyclopropylaminederivatives that exhibit potent LSD1 inhibitory activity while beingdevoid of or having substantially reduced MAO-A inhibitory activity.

In view of the lack of adequate treatments for conditions such as cancerand neurodegeneration, there is a desperate need for disease modifyingdrugs and drugs that work by inhibiting novel targets. There is thus aneed for the development of LSD1 inhibitors, particularly those whichselectively inhibit LSD1.

SUMMARY OF THE INVENTION

The present invention relates to the identification of compounds andtheir use in treating or preventing diseases. The invention provides(hetero)aryl cyclopropylamine compounds, including the compounds ofFormula I, Ia, Ia-1, Ib and Ic, and particularly the compounds I, Ia andIa-1, as described and defined herein. The present inventionparticularly provides a compound of Formula I, Ia, Ia-1, Ib and Ic, andparticularly a compound of Formula I, Ia and Ia-1, pharmaceuticalcompositions comprising a compound of Formula I, Ia, Ia-1, Ib or Ic, andparticularly a compound of Formula I, Ia or Ia-1, and a pharmaceuticallyacceptable carrier, and their uses for treating diseases. One use of thecompound of Formula I, Ia, Ia-1, Ib and Ic is for treating or preventingcancer. Another use for the compound of Formula I, Ia, Ia-1, Ib and Icis to inhibit LSD1. The invention thus relates to a compound of FormulaI, Ia, Ia-1, Ib or Ic, and particularly a compound of Formula I, Ia orIa-1, for use in treating or preventing human disease. The presentinvention further relates to a compound of Formula I, Ia, Ia-1, Ib orIc, and particularly a compound of Formula I, Ia and Ia-1, for use intreating or preventing cancer. The present invention further relates toa compound of Formula I, Ia, Ia-1, Ib or Ic, and particularly a compoundof Formula I, Ia and Ia-1, for use in treating or preventing aneurological disease. The present invention further relates to acompound of Formula I, Ia, Ia-1, Ib or Ic, and particularly a compoundof Formula I, Ia and Ia-1, for use in treating or preventing a viralinfection.

Accordingly, the present invention provides a compound of Formula I:

wherein:A is aryl or heteroaryl, wherein said aryl or said heteroaryl isoptionally substituted with one or more R¹;B is hydrogen, R¹ or -L-E;E is aryl or heteroaryl, wherein said aryl or said heteroaryl isoptionally substituted with one or more R²;L is a bond, —O—, —NH—, —N(C₁₋₄ alkyl)-, C₁₋₄ alkylene or heteroC₁₋₄alkylene;D is a cycloalkyl group having from 4 to 7 C atoms, wherein saidcycloalkyl group has one or two substituents R³ and is furtheroptionally substituted with one or more R⁴, and wherein the cycloalkylgroup optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group, wherein p is 1 or 2 and each R^(a)        independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group via a single carbon        atom common to both rings, and wherein said second ring is        optionally substituted with one or more R⁶;        each R¹ is independently selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,        C₂₋₈ alkynyl, cyclyl, amino, amido, hydroxyl, nitro, halo,        haloC₁₋₈ alkyl, haloC₁₋₈ alkoxy, cyano, sulfinyl, sulfonyl,        sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, O-carboxy, C-carboxy,        carbamate and urea;        each R² is independently selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,        C₂₋₈ alkynyl, cyclyl, amino, amido, hydroxyl, nitro, halo,        haloC₁₋₈ alkyl, haloC₁₋₈ alkoxy, cyano, sulfinyl, sulfonyl,        sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, O-carboxy, C-carboxy,        carbamate and urea;        each R³ is independently selected from —NR⁷R⁸, —NHOH, —NR⁹COR¹⁰,        —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —OH,        —CONR⁷R⁸, oxo, —C₁₋₄ alkylene-NR⁷R⁸, —C₁₋₄ alkylene-NHOH, —C₁₋₄        alkyene-NR⁹COR¹⁰, —C₁₋₄ alkylene-NR⁹SO₂R¹⁰, —C₁₋₄        alkylene-NR⁹COOR¹⁰, —C₁₋₄ alkylene-NR⁹CONR⁷R⁸, —C₁₋₄        alkylene-NR⁹SO₂NR⁷R⁸, —C₁₋₄ alkylene-OH and —C₁₋₄        alkylene-CONR⁷R⁸;        each R⁴ and each R⁶ is independently selected from C₁₋₈ alkyl,        halo, haloC₁₋₈ alkyl, haloC₁₋₈ alkoxy and C₁₋₈ alkoxy;        each R⁵ is independently selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,        C₂₋₈ alkynyl, cyclyl, amino, amido, hydroxyl, nitro, halo,        haloC₁₋₈ alkyl, haloC₁₋₈ alkoxy, cyano, sulfinyl, sulfonyl,        sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, O-carboxy, C-carboxy,        carbamate and urea;        each R⁷ and each R⁸ is independently selected from hydrogen,        C₁₋₈ alkyl, R¹²R¹³N—C₁₋₈ alkyl and hydroxyC₁₋₈ alkyl, or R⁷ and        R⁸ are linked together to form, along with the N atom to which        they are bound, a saturated 3- to 7-membered heterocyclic ring        which optionally contains one further heteroatom selected from        N, O and S, wherein one or more C atoms in said heterocyclic        ring are optionally oxidized to form CO groups, wherein one or        more S atoms in said heterocyclic ring, if present, are        optionally oxidized to form independently SO groups or SO₂        groups, and wherein said heterocyclic ring is optionally        substituted with one or more R¹¹;        each R⁹ is independently selected from hydrogen and C₁₋₄ alkyl;        each R¹⁰ is independently selected from C₁₋₈ alkyl, haloC₁₋₈        alkyl, cyclyl and cyclylC₁₋₈ alkyl, wherein said cyclyl or the        cyclyl moiety comprised in said cyclylC₁₋₈ alkyl is optionally        substituted with one or more R¹⁴;        each R¹¹ is independently selected from C₁₋₈ alkyl, halo, C₁₋₈        alkoxy, hydroxyl and —NR¹²R¹³;        each R¹² and each R¹³ is independently selected from hydrogen        and C₁₋₈ alkyl;        each R¹⁴ is independently selected from C₁₋₈ alkyl, C₂₋₈        alkenyl, C₂₋₈ alkynyl, amino, amido, hydroxyl, nitro, halo,        haloC₁₋₈ alkyl, haloC₁₋₈ alkoxy, cyano, sulfinyl, sulfonyl,        sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, O-carboxy, C-carboxy,        carbamate and urea; and        each R^(w), R^(x), R^(y) and R^(z) is independently selected        from hydrogen, halo and C₁₋₄ alkyl;        with the proviso that the following compounds are excluded:

-   2-((2-phenylcyclopropyl)amino)cycloheptanol, and

-   2-((2-phenylcyclopropyl)amino)cyclopentanol.

It is furthermore preferred that the compound2-((2-phenylcyclopropyl)amino)cyclohexanol is excluded.

In another embodiment, the present invention provides a compound ofFormula I wherein R^(w), R^(x), R^(y) and R^(z) are each hydrogen, i.e.a compound of formula Ia:

wherein:A is aryl or heteroaryl, wherein said aryl or said heteroaryl isoptionally substituted with one or more R¹;B is hydrogen, R¹ or -L-E;E is aryl or heteroaryl, wherein said aryl or said heteroaryl isoptionally substituted with one or more R²;L is a bond, —O—, —NH—, —N(C₁₋₄ alkyl)-, C₁₋₄ alkylene or heteroC₁₋₄alkylene;D is a cycloalkyl group having from 4 to 7 C atoms, wherein saidcycloalkyl group has one or two substituents R³ and is furtheroptionally substituted with one or more R⁴, and wherein the cycloalkylgroup optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group, wherein p is 1 or 2 and each R^(a)        independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group via a single carbon        atom common to both rings, and wherein said second ring is        optionally substituted with one or more R⁶;        each R¹ is independently selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,        C₂₋₈ alkynyl, cyclyl, amino, amido, hydroxyl, nitro, halo,        haloC₁₋₈ alkyl, haloC₁₋₈ alkoxy, cyano, sulfinyl, sulfonyl,        sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, O-carboxy, C-carboxy,        carbamate and urea;        each R² is independently selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,        C₂₋₈ alkynyl, cyclyl, amino, amido, hydroxyl, nitro, halo,        haloC₁₋₈ alkyl, haloC₁₋₈ alkoxy, cyano, sulfinyl, sulfonyl,        sulfonamide, C₁₋₄ alkoxy, acyl, carboxyl, O-carboxy, C-carboxy,        carbamate and urea;        each R³ is independently selected from —NR⁷R⁸, —NHOH, —NR⁹COR¹⁰,        —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —OH,        —CONR⁷R⁸, oxo, —C₁₋₄ alkylene-NR⁷R⁸, —C₁₋₄ alkylene-NHOH, —C₁₋₄        alkyene-NR⁹COR¹⁰, —C₁₋₄ alkylene-NR⁹SO₂R¹⁰, —C₁₋₄        alkylene-NR⁹COOR¹⁰, —C₁₋₄ alkylene-NR⁹CONR⁷R⁸, —C₁₋₄        alkylene-NR⁹SO₂NR⁷R⁸, —C₁₋₄ alkylene-OH and —C₁₋₄        alkylene-CONR⁷R⁸;        each R⁴ and each R⁶ is independently selected from C₁₋₈ alkyl,        halo, haloC₁₋₈ alkyl, haloC₁₋₈ alkoxy and C₁₋₈ alkoxy;        each R⁵ is independently selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,        C₂₋₈ alkynyl, cyclyl, amino, amido, hydroxyl, nitro, halo,        haloC₁₋₈ alkyl, haloC₁₋₈ alkoxy, cyano, sulfinyl, sulfonyl,        sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, O-carboxy, C-carboxy,        carbamate and urea;        each R⁷ and each R⁸ is independently selected from hydrogen,        C₁₋₈ alkyl, R¹²R¹³N—C₁₋₈ alkyl and hydroxyC₁₋₈ alkyl, or R⁷ and        R⁸ are linked together to form, along with the N atom to which        they are bound, a saturated 3- to 7-membered heterocyclic ring        which optionally contains one further heteroatom selected from        N, O and S, wherein one or more C atoms in said heterocyclic        ring are optionally oxidized to form CO groups, wherein one or        more S atoms in said heterocyclic ring, if present, are        optionally oxidized to form independently SO groups or SO₂        groups, and wherein said heterocyclic ring is optionally        substituted with one or more R¹¹;        each R⁹ is independently selected from hydrogen and C₁₋₄ alkyl;        each R¹⁰ is independently selected from C₁₋₈ alkyl, haloC₁₋₈        alkyl, cyclyl and cyclylC₁₋₈ alkyl, wherein said cyclyl or the        cyclyl moiety comprised in said cyclylC₁₋₈ alkyl is optionally        substituted with one or more R¹⁴;        each R¹¹ is independently selected from C₁₋₈ alkyl, halo, C₁₋₈        alkoxy, hydroxyl and —NR¹²R¹³;        each R¹² and each R¹³ is independently selected from hydrogen        and C₁₋₈ alkyl; and        each R¹⁴ is independently selected from C₁₋₈ alkyl, C₂₋₈        alkenyl, C₂₋₈ alkynyl, amino, amido, hydroxyl, nitro, halo,        haloC₁₋₈ alkyl, haloC₁₋₈ alkoxy, cyano, sulfinyl, sulfonyl,        sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, O-carboxy, C-carboxy,        carbamate and urea;        with the proviso that the following compounds are excluded:

-   2-((2-phenylcyclopropyl)amino)cycloheptanol, and

-   2-((2-phenylcyclopropyl)amino)cyclopentanol.

It is furthermore preferred that the compound2-((2-phenylcyclopropyl)amino)cyclohexanol is excluded.

In another embodiment, the invention provides a compound of formula Iaas defined above wherein the substituents of the cyclopropyl moiety -A-Band —NH-D are in the trans-configuration, i.e. a compound of formulaIa-1:

wherein the groups and variables of formula Ia-1, including A, B, D, E,L, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴, areas defined above in relation to a compound of formula Ia, with theproviso that the following compounds are excluded:

-   2-((2-phenylcyclopropyl)amino)cycloheptanol, and-   2-((2-phenylcyclopropyl)amino)cyclopentanol.

It is furthermore preferred that the compound2-((2-phenylcyclopropyl)amino)cyclohexanol is excluded.

The above chemical representation for a compound of formula Ia-1 doesnot intend to indicate absolute stereochemistry of the two chiralcenters on the cyclopropyl ring, but only their relative stereochemistry(which is trans). Thus a compound of formula Ia-1 could likewise berepresented as

A compound of formula Ia-1 therefore relates to the individual opticallyactive trans isomers as well as any mixtures thereof.

In another embodiment, the invention provides a compound of formula I asdefined above wherein each R^(w), R^(x), R^(y) and R^(z) isindependently selected from hydrogen, halo and C₁₋₄ alkyl, with theproviso that at least one of R^(w), R^(x), R^(y) and R^(z) is nothydrogen; that compound is referred to as a compound of formula Ib inthe following. In a more preferred embodiment, R^(w) is selected fromhalo and C₁₋₄ alkyl, preferably from fluoro and methyl, and each R^(x),R^(y) and R^(z) is hydrogen. A compound of formula I wherein R^(w) isselected from halo and C₁₋₄ alkyl, preferably from fluoro and methyl,and each R^(x), R^(y) and R^(z) is hydrogen is referred to as a compoundof formula Ic in the following.

Also included within the scope of the invention are all isomers,including all stereoisomers and mixtures thereof, of the compounds offormula I, Ia, Ia-1, Ib and Ic (as defined herein). All salts and allsolvates, preferably pharmaceutically acceptable salts and solvates, ofthe compounds of formula I, Ia, Ia-1, Ib and Ic are also encompassedwithin the scope of the invention. Furthermore, all physical forms(including amorphous and crystalline forms) of any such compounds arealso encompassed within the scope of the invention. Any reference to acompound of formula I, Ia, Ia-1, Ib or Ic, respectively, should beconstrued, unless otherwise indicated, as a reference to a compound offormula I, Ia, Ia-1, Ib or Ic (respectively), any isomer thereof(including any stereoisomer thereof or any mixtures thereof), any saltthereof (including any pharmaceutically acceptable salt thereof), anysolvate thereof (including any pharmaceutically acceptable solvatethereof), and any physical form thereof.

The compounds of formula Ia, including also the compounds of formulaIa-1, are particularly preferred compounds according to the presentinvention. The most preferred compounds of the invention are thecompounds of formula Ia-1.

Any chemical drawing or formula given herein is intended to representunlabeled forms as well as isotopically labeled forms of the compoundsof the invention. Isotopically labeled compounds have structuresdepicted by the formulas given herein except that one or more atoms arereplaced by an atom having a selected atomic mass or mass number.Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I, respectively.Such isotopically labelled compounds are useful in metabolic studies(preferably with ¹⁴C), reaction kinetic studies (with, for example ²H or³H), detection or imaging techniques [such as positron emissiontomography (PET) or single-photon emission computed tomography (SPECT)]including drug or substrate tissue distribution assays, or inradioactive treatment of patients. In particular, an ¹⁸F or ¹¹C labeledcompound may be particularly preferred for PET or SPECT studies.Further, substitution with heavier isotopes such as deuterium (i.e., ²H)may afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements. Particularly preferred are the deuterated forms ofthe compounds of the invention, i.e. a compound of formula I, Ia, Ia-1,Ib and Ic above wherein one or more hydrogen atoms has been replacedwith deuterium. Isotopically labeled compounds of the invention cangenerally be prepared by carrying out the procedures disclosed in theschemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent. In addition to the unlabeled form, allisotopically labeled forms of the compounds of formula I, Ia, Ia-1, Iband Ic are included within the scope of the invention.

In a compound of formula I, Ia, Ib or Ic the substituents -A-B and —NH-Don the cyclopropyl moiety are preferably in the trans-configuration.

The compounds of formula I, Ia, Ia-1, Ib and Ic are potent inhibitors ofLSD1 and therefore can be useful for the treatment or prevention of anydisease associated with LSD1.

The invention thus provides a pharmaceutical composition comprising acompound of Formula I, Ia, Ia-1, Ib or Ic and a pharmaceuticallyacceptable carrier.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound of formula I

wherein the groups and variables in formula I, including A, B, D, R^(w),R^(x), R^(y) and R^(z), are as defined above, with the proviso that thefollowing compounds are excluded:

-   2-((2-phenylcyclopropyl)amino)cycloheptanol, and-   2-((2-phenylcyclopropyl)amino)cyclopentanol;    and a pharmaceutically acceptable carrier.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a compound of formula Ia

wherein the groups and variables in formula Ia, including A, B, and D,are as defined above, with the proviso that the following compounds areexcluded:

-   2-((2-phenylcyclopropyl)amino)cycloheptanol, and-   2-((2-phenylcyclopropyl)amino)cyclopentanol;    and a pharmaceutically acceptable carrier.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a compound of formula Ia-1

wherein the groups and variables in formula Ia-1, including A, B, and D,are as defined above, with the proviso that the following compounds areexcluded:

-   2-((2-phenylcyclopropyl)amino)cycloheptanol, and-   2-((2-phenylcyclopropyl)amino)cyclopentanol;    and a pharmaceutically acceptable carrier.

Preferred embodiments of the compounds of Formula I, Ia, Ia-1, Ib andIc, e. g. for use in the compositions of the invention, are defined anddescribed herein below in more detail.

In another aspect, the invention provides a method of treating orpreventing a disease comprising administering, to a patient (preferablya human) in need of such treatment or prevention, an amount of acompound of Formula I, Ia, Ia-1, Ib or Ic (as described above or asdefined in the embodiments thereof described below) effective to treator prevent said disease. In one embodiment, such disease is a diseaseassociated with LSD1.

In a related aspect, the invention provides a compound of Formula I, Ia,Ia-1, Ib or Ic (as described above or as defined in the embodimentsthereof as described below) for use as a medicament. In a more specificembodiment, the invention provides a compound of Formula I, Ia, Ia-1, Ibor Ic for use in the treatment or prevention of a disease associatedwith LSD1.

Thus, in one embodiment, the invention provides a compound of formula I

wherein the groups and variables in formula I, including A, B, D, R^(w),R^(x), R^(y) and R^(z), are as defined above, with the proviso that thefollowing compounds are excluded:

-   2-((2-phenylcyclopropyl)amino)cycloheptanol, and-   2-((2-phenylcyclopropyl)amino)cyclopentanol;    for use as a medicament.

In another embodiment, the invention provides a compound of formula Ia

wherein the groups and variables in formula Ia, including A, B, and D,are as defined above, with the proviso that the following compounds areexcluded:

-   2-((2-phenylcyclopropyl)amino)cycloheptanol, and-   2-((2-phenylcyclopropyl)amino)cyclopentanol;    for use as a medicament.

In another embodiment, the invention provides a compound of formula Ia-1

wherein the groups and variables in formula Ia-1, including A, B, and D,are as defined above, with the proviso that the following compounds areexcluded:

-   2-((2-phenylcyclopropyl)amino)cycloheptanol, and-   2-((2-phenylcyclopropyl)amino)cyclopentanol;    for use as a medicament.

In yet another aspect, the invention provides a method of inhibitingLSD1 activity comprising administering, to a patient in need oftreatment, an amount of a compound of Formula I, Ia, Ia-1, Ib or Icsufficient to inhibit LSD1 activity. Preferably the patient is a human.In a related aspect, the invention provides a compound of Formula I, Ia,Ia-1, Ib or Ic as herein defined for use as a LSD1 inhibitor. Preferredembodiments of the compounds of Formula I, Ia, Ia-1, Ib or Ic for useherein are as described in more detail below.

In another aspect, the invention provides a method of treating orpreventing cancer comprising administering, to a patient (preferably ahuman) in need of such treatment or prevention, an amount of a compoundof Formula I, Ia, Ia-1, Ib or Ic (as defined above or as defined in theembodiments described in more detail herein) sufficient to treat orprevent such cancer. In a related aspect, the invention provides amethod of treating or preventing a cancer wherein said cancer is chosenfrom breast cancer, lung cancer, prostate cancer, colorectal cancer,brain cancer, skin cancer, blood cancer (e.g., leukemia, including, forexample, acute myelogenous leukemia (AML), chronic myelogenous leukemia(CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia,chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL),or hairy cell leukemia), lymphoma and myeloma, comprising administeringto a patient (preferably a human) in need of such treatment orprevention, an amount of a compound of Formula I, Ia, Ia-1, Ib or Ic (asdefined above or as defined in the embodiments described in more detailherein) sufficient to treat or prevent such cancer. In an even morespecific aspect, said cancer is chosen from prostate, brain, colorectal,lung, breast, skin, and blood cancer. In one specific aspect, the canceris prostate cancer. In one specific aspect, the cancer is lung cancer.In one specific aspect, the cancer is brain cancer. In one specificaspect, the cancer is blood cancer (e.g., leukemia, including, forexample, acute myelogenous leukemia (AML), chronic myelogenous leukemia(CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia,chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL),or hairy cell leukemia). In one specific aspect, the cancer is breastcancer. In one specific aspect, the cancer is colorectal cancer. In onespecific aspect, the cancer is lymphoma. In one specific aspect, thecancer is myeloma. In a preferred embodiment, the method comprisesadministering a therapeutically effective amount of a compound ofFormula I, Ia, Ia-1, Ib or Ic sufficient for treating or preventing saidcancer. In a preferred aspect, the therapeutically effective amount of acompound of Formula I, Ia, Ia-1, Ib or Ic is an amount sufficient toinhibit LSD1. In another preferred aspect, the therapeutically effectiveamount is an amount sufficient to modulate histone methylation levels.In another preferred aspect, the therapeutically effective amount is anamount sufficient to modulate histone-3 lysine-4 methylation levels. Inanother preferred aspect, the therapeutically effective amount is anamount sufficient to modulate histone-3 lysine-9 methylation levels.While the present invention relates to both the treatment and theprevention of cancer, the treatment of cancer is particularly preferred.

Thus, in one embodiment, the invention provides a method of treating orpreventing cancer comprising administering, to a patient (preferably ahuman) in need of such treatment or prevention, an amount of a compoundof Formula I

wherein the groups and variables in formula I, including A, B, D, R^(w),R^(x), R^(y) and R^(z), are as defined above, with the proviso that thefollowing compounds are excluded:

-   2-((2-phenylcyclopropyl)amino)cycloheptanol, and-   2-((2-phenylcyclopropyl)amino)cyclopentanol.

In another embodiment, the invention provides a method of treating orpreventing cancer comprising administering, to a patient (preferably ahuman) in need of such treatment or prevention, an amount of a compoundof Formula Ia

wherein the groups and variables in formula Ia, including A, B, and D,are as defined above, with the proviso that the following compounds areexcluded:

-   2-((2-phenylcyclopropyl)amino)cycloheptanol, and-   2-((2-phenylcyclopropyl)amino)cyclopentanol.

In another embodiment, the invention provides a method of treating orpreventing cancer comprising administering, to a patient (preferably ahuman) in need of such treatment or prevention, an amount of a compoundof Formula Ia-1

wherein the groups and variables in formula Ia-1, including A, B, and D,are as defined above, with the proviso that the following compounds areexcluded:

-   2-((2-phenylcyclopropyl)amino)cycloheptanol, and-   2-((2-phenylcyclopropyl)amino)cyclopentanol.

In a related aspect, the invention provides a compound of Formula I, Ia,Ia-1, Ib or Ic (as defined above or as defined in the embodimentsdescribed in more detail herein), for use in the treatment or preventionof cancer. In another related aspect, the invention provides a compoundof Formula I, Ia, Ia-1, Ib or Ic for use in the treatment or preventionof a cancer wherein said cancer is chosen from breast cancer, lungcancer, prostate cancer, colorectal cancer, brain cancer, skin cancer,blood cancer (e.g., leukemia, including, for example, acute myelogenousleukemia (AML), chronic myelogenous leukemia (CML), chronic neutrophilicleukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia(CLL), acute lymphoblastic leukemia (ALL), or hairy cell leukemia),lymphoma and myeloma. In a more specific aspect, said cancer is chosenfrom prostate, brain, colorectal, lung, breast, skin, and blood cancer.In one specific aspect, the cancer is prostate cancer. In one specificaspect, the cancer is lung cancer. In one specific aspect, the cancer isbrain cancer. In one specific aspect, the cancer is blood cancer (e.g.,leukemia, including, for example, acute myelogenous leukemia (AML),chronic myelogenous leukemia (CML), chronic neutrophilic leukemia,chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acutelymphoblastic leukemia (ALL), or hairy cell leukemia). In one specificaspect, the cancer is breast cancer. In one specific aspect, the canceris colorectal cancer. In one specific aspect, the cancer is lymphoma. Inone specific aspect, the cancer is myeloma. In preferred embodiment, atherapeutically effective amount of a compound of Formula I, Ia, Ia-1,Ib or Ic sufficient for treating or preventing said cancer isadministered. In a preferred aspect, the therapeutically effectiveamount of a compound of Formula I, Ia, Ia-1, Ib or Ic is an amountsufficient to inhibit LSD1. In another preferred aspect, thetherapeutically effective amount is an amount sufficient to modulatehistone methylation levels. In another preferred aspect, thetherapeutically effective amount is an amount sufficient to modulatehistone-3 lysine-4 methylation levels. In another preferred aspect, thetherapeutically effective amount is an amount sufficient to modulatehistone-3 lysine-9 methylation levels.

Thus, in one embodiment, the invention provides a compound of formula I

wherein the groups and variables in formula I, including A, B, D, R^(w),R^(x), R^(y) and R^(z), are as defined above, with the proviso that thefollowing compounds are excluded:

-   2-((2-phenylcyclopropyl)amino)cycloheptanol, and-   2-((2-phenylcyclopropyl)amino)cyclopentanol;    for use in the treatment or prevention of cancer.

In another embodiment, the invention provides a compound of formula Ia

wherein the groups and variables in formula Ia, including A, B, and D,are as defined above, with the proviso that the following compounds areexcluded:

-   2-((2-phenylcyclopropyl)amino)cycloheptanol, and-   2-((2-phenylcyclopropyl)amino)cyclopentanol;    for use in the treatment or prevention of cancer.

In another embodiment, the invention provides a compound of formula Ia-1

wherein the groups and variables in formula Ia-1, including A, B, and D,are as defined above, with the proviso that the following compounds areexcluded:

-   2-((2-phenylcyclopropyl)amino)cycloheptanol, and-   2-((2-phenylcyclopropyl)amino)cyclopentanol;    for use in the treatment or prevention of cancer.

In another aspect, the invention provides a method of treating orpreventing a neurological disease (e.g., a neurodegenerative disease)comprising administering, to a patient in need of such treatment orprevention, an amount of a compound of Formula I, Ia, Ia-1, Ib or Ic (asdefined above or in the embodiments described in more detail herein)sufficient to treat or prevent said neurological disease. In a relatedaspect, the invention provides a method of treating or preventing aneurological disease wherein said neurological disease is selected fromdepression, Alzheimer's disease, Huntington disease, Parkinson'sdisease, Amyotrophic Lateral Sclerosis, Dementia with Lewy Bodies, orFrontotemporal Dementia, particularly from depression, Alzheimer'sdisease, Huntington disease, Parkinson's disease, or Dementia with LewyBodies, comprising administering to a patient (preferably a human) inneed of such treatment or prevention, an amount of a compound of FormulaI, Ia, Ia-1, Ib or Ic (as defined above or as defined in the embodimentsdescribed in more detail herein) sufficient to treat or prevent suchneurological disease. In a preferred embodiment, the method comprisesadministering a therapeutically effective amount of a compound ofFormula I, Ia, Ia-1, Ib or Ic sufficient for treating or preventing saidneurological disease. In a preferred aspect, the therapeuticallyeffective amount of a compound of Formula I, Ia, Ia-1, Ib or Ic is anamount sufficient to inhibit LSD1. In another preferred aspect, thetherapeutically effective amount is an amount sufficient to modulatehistone methylation levels. In another preferred aspect, thetherapeutically effective amount is an amount sufficient to modulatehistone-3 lysine-4 methylation levels. In another preferred aspect, thetherapeutically effective amount is an amount sufficient to modulatehistone-3 lysine-9 methylation levels.

In another related aspect, the invention provides a compound of FormulaI, Ia, Ia-1, Ib or Ic (as defined above or in the embodiments describedin more detail herein) for use in the treatment or prevention of aneurological disease (e.g., a neurodegenerative disease). In oneembodiment, said neurological disease is selected from depression,Alzheimer's disease, Huntington disease, Parkinson's disease,Amyotrophic Lateral Sclerosis, Dementia with Lewy Bodies andFrontotemporal Dementia, particularly from depression, Alzheimer'sdisease, Huntington disease, Parkinson's disease and Dementia with LewyBodies. In a preferred embodiment, a therapeutically effective amount ofa compound of Formula I, Ia, Ia-1, Ib or Ic sufficient for treating orpreventing said neurological disease is administered. In a preferredaspect, the therapeutically effective amount of a compound of Formula I,Ia, Ia-1, Ib or Ic is an amount sufficient to inhibit LSD1. In anotherpreferred aspect, the therapeutically effective amount is an amountsufficient to modulate histone methylation levels. In another preferredaspect, the therapeutically effective amount is an amount sufficient tomodulate histone-3 lysine-4 methylation levels. In another preferredaspect, the therapeutically effective amount is an amount sufficient tomodulate histone-3 lysine-9 methylation levels.

In another aspect, the invention provides a method of treating orpreventing a viral infection comprising administering to a patient inneed thereof (preferably a human) an amount of a compound of Formula I,Ia, Ia-1, Ib or Ic (as defined above or in the embodiments described inmore detail herein) sufficient to treat or prevent said viral infection.In a related aspect, the invention also provides a compound of FormulaI, Ia, Ia-1, Ib or Ic (as defined above or in the embodiments describedin more detail herein) for use in treating or preventing a viralinfection. In one specific embodiment, the viral infection is aherpesvirus infection. In a more specific embodiment, the herpesvirusinfection is caused by and/or associated with a herpesvirus chosen fromHSV-1, HSV-2, and Epstein-Barr virus. In another embodiment, the viralinfection is caused by and/or associated with HIV. In anotherembodiment, the viral infection is caused by and/or associated with aHepadnavirus (i.e. a virus of the Hepadnaviridae family), particularlyHepatitis B virus (HBV). In another embodiment, the viral infection iscaused by and/or associated with a Flavivirus (i.e. a virus of theFlaviviridae family), particularly Hepatitis C virus (HCV), yellow fevervirus, West Nile virus, Dengue virus or Japanese encephalitis virus, andmore preferably HCV. In an even more specific embodiment, the inventionprovides a method for treating or preventing viral reactivation afterlatency, the method comprising administering to an individual(preferably a human) a compound of Formula I, Ia, Ia-1, Ib or Ic (asdefined above or in the embodiments described in more detail herein).Accordingly, the invention also provides a compound of Formula I, Ia,Ia-1, Ib or Ic (as defined above or in the embodiments described in moredetail herein) for use in treating or preventing viral reactivationafter latency. In a specific embodiment, the virus that is reactivatingis a herpesvirus. In a more specific embodiment, the herpesvirus that isreactivating is chosen from HSV-1, HSV-2, and Epstein-Barr virus. In aneven more specific embodiment, the virus that is reactivating is HSV. Ina further specific embodiment, the virus that is reactivating is HIV.

In still another aspect, the invention provides the use of a compound ofFormula I, Ia, Ia-1, Ib or Ic (as defined above or in the embodimentsdescribed in more detail herein) for the manufacture of a medicament forthe treatment or prevention of cancer. In a preferred embodiment, saidcancer is chosen from breast cancer, lung cancer, prostate cancer,colorectal cancer, brain cancer, skin cancer, blood cancer (e.g.,leukemia, including, for example, acute myelogenous leukemia (AML),chronic myelogenous leukemia (CML), chronic neutrophilic leukemia,chronic eosinophilic leukemia, chronic lymphocytic leukemia (CLL), acutelymphoblastic leukemia (ALL), or hairy cell leukemia), lymphoma andmyeloma.

In still another aspect, the invention provides the use of a compound ofFormula I, Ia, Ia-1, Ib or Ic (as defined above or in the embodimentsdescribed in more detail herein) for the manufacture of a medicament forthe treatment or prevention of a neurological disease (e.g., aneurodegenerative disease). In a preferred embodiment said neurologicaldisease is selected from depression, Alzheimer's disease, Huntingtondisease, Parkinson's disease, Amyotrophic Lateral Sclerosis, Dementiawith Lewy Bodies, or Frontotemporal Dementia, particularly fromdepression, Alzheimer's disease, Huntington disease, Parkinson'sdisease, and Dementia with Lewy Bodies.

In still another aspect, the invention provides the use of a compound ofFormula I, Ia, Ia-1, Ib or Ic (as defined above or in the embodimentsdescribed in more detail herein) for the manufacture of a medicament forthe treatment or prevention of a viral infection. In a preferredembodiment, said viral infection is a herpesvirus infection (e.g., aherpesvirus infection caused by and/or associated with a herpesviruschosen from HSV-1, HSV-2, and Epstein-Barr virus) or a viral infectioncaused by and/or associated with HIV. In another preferred embodiment,said viral infection is caused by and/or associated with a Hepadnavirus,particularly Hepatitis B virus (HBV). In another embodiment, said viralinfection is caused by and/or associated with a Flavivirus, particularlyHepatitis C virus (HCV), yellow fever virus, West Nile virus, Denguevirus or Japanese encephalitis virus, and more preferably HCV.

In still another aspect, the invention provides the use of a compound ofFormula I, Ia, Ia-1, Ib or Ic (as defined above or in the embodimentsdescribed in more detail herein) for the manufacture of a medicament forthe treatment or prevention of viral reactivation after latency. In apreferred embodiment, the virus that is reactivating is a herpesvirus(e.g., HSV-1, HSV-2, or Epstein-Barr virus), HSV, or HIV.

In still another aspect, the invention provides a method for identifyinga compound which is a selective inhibitor of LSD1, the method comprisingselecting or providing a compound of Formula I, Ia, Ia-1, Ib or Ic asdefined herein, and determining the ability of the compound to inhibitLSD1 and MAO-A and/or MAO-B, wherein a compound that inhibits LSD1 to agreater extent than MAO-A and/or MAO-B is identified as a LSD1 selectiveinhibitor. The compound of this aspect that is an LSD1 inhibitor can beused to treat disease, particularly human disease.

In another aspect, the invention provides a process for the preparationof a compound of formula I, or a salt thereof, which comprises reactinga compound of formula II

wherein A, B, R^(w), R^(x), R^(y), R^(z) have the meaning disclosedabove in relation to a compound of formula I, with a compound of formulaIII

wherein D has the meaning disclosed above in relation to a compound offormula I and wherein the group(s) R³ on ring D are optionally protectedwith a protecting group,in the presence of a reducing agent, followed by the removal of anyprotecting group that may be present. The reducing agent may be, e.g., aborohydride, such as sodium borohydride or sodium triacetoxyborohydride.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention pertains. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. In case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

Other features and advantages of the invention will be apparent from thefollowing detailed description, and from the claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the identification of compounds andtheir use in treating and preventing diseases. The present inventionprovides compounds of Formula I, Ia, Ia-1, Ib and Ic, pharmaceuticalcompositions comprising a compound of Formula I, Ia, Ia-1, Ib or Ic anda pharmaceutically acceptable carrier, and their use for treatingdiseases. One use of the compounds of Formula I, Ia, Ia-1, Ib and Ic isfor treating cancer.

The present invention provides a compound of Formula I

In a compound of formula I, each R^(w), R^(x), R^(y) and R^(z) isindependently selected from hydrogen, halo and C₁₋₄ alkyl. In oneembodiment, each R^(w), R^(x), R^(y) and R^(z) is independently selectedfrom hydrogen, fluoro and C₁₋₄ alkyl, preferably from hydrogen, fluoroand methyl. In another embodiment, each R^(w), R^(x), R^(y) and R^(z) isindependently selected from hydrogen and fluoro. In another embodiment,R^(w) is fluoro and each R^(x), R^(y) and R^(z) is independentlyselected from hydrogen, halo and C₁₋₄ alkyl; preferably, R^(w) is fluoroand each R^(x), R^(y) and R^(z) is hydrogen. In another embodiment,R^(z) is fluoro and each R^(w), R^(x) and R^(y) is independentlyselected from hydrogen, halo and C₁₋₄ alkyl; preferably, R^(z) is fluoroand each R^(w), R^(x) and R^(y) is hydrogen. In another embodiment,R^(w) and R^(z) are fluoro and each R^(x) and R^(y) is independentlyselected from hydrogen, halo and C₁₋₄ alkyl; preferably, R^(w) and R^(z)are fluoro and each R^(x) and R^(y) is hydrogen. In a preferredembodiment, R^(w) is selected from hydrogen, halo and C₁₋₄ alkyl,preferably from hydrogen, fluoro and methyl, and each R^(x), R^(y) andR^(z) is hydrogen. In a more preferred embodiment, each R^(w), R^(x),R^(y) and R^(z) is hydrogen. A compound of formula I wherein each R^(w),R^(x), R^(y) and R^(z) is hydrogen is a compound of formula Ia, whichcan be depicted as follows:

In another embodiment, in a compound of formula I each R^(w), R^(x),R^(y) and R^(z) is independently selected from hydrogen, halo and C₁₋₄alkyl with the proviso that at least one is not hydrogen, this is acompound of formula Ib. In a more preferred embodiment, R^(w) isselected from halo and C₁₋₄ alkyl, preferably fluoro and methyl, andeach R^(x), R^(y) and R^(z) is hydrogen. A compound of formula I whereinR^(w) is selected from halo and C₁₋₄ alkyl, preferably fluoro andmethyl, and each R^(x), R^(y) and R^(z) is hydrogen is a compound offormula Ic. Preferably, in a compound of formula Ic R^(w) is methyl.

In a compound of formula I, Ia, Ia-1, Ib or Ic, the group A is aryl orheteroaryl, wherein said aryl or said heteroaryl is optionallysubstituted with one or more R¹. In one embodiment, A is aryl(preferably phenyl or naphthyl) optionally substituted with one or moreR¹. In a specific embodiment, A is phenyl optionally substituted withone or more R¹. In another specific embodiment, A is naphthyl optionallysubstituted with one or more R¹. In another embodiment, A is heteroaryl(preferably monocyclic heteroaryl), optionally substituted with one ormore R¹. In a preferred embodiment, A is phenyl, naphthyl or monocyclicheteroaryl, wherein said phenyl, naphthyl or monocyclic heteroaryl isoptionally substituted with one or more R¹. Preferably, A is monocyclicaryl (i.e. phenyl) or monocyclic heteroaryl, wherein said monocyclicaryl or said monocyclic heteroaryl is optionally substituted with one ormore R¹. More preferably, A is phenyl, pyridyl, thiophenyl, pyrrolyl,furanyl, or thiazolyl, wherein A (i.e. said phenyl, said pyridyl, saidthiophenyl, said pyrrolyl, said furanyl, or said thiazolyl) isoptionally substituted with one or more R¹. More preferably, A isphenyl, pyridyl, thiazolyl or thiophenyl, wherein A (i.e. said phenyl,said pyridyl, said thiazolyl or said thiophenyl) is optionallysubstituted with one or more R¹. Still more preferably, A is phenyl,pyridyl or thiazolyl, wherein A is optionally substituted with one ormore R¹. Even more preferably, A is phenyl, 3-pyridyl or 5-thiazolyl, asshown below:

wherein A is optionally substituted with one or more R¹. In oneembodiment, A is phenyl or pyridyl, preferably phenyl or 3-pyridyl. Inanother embodiment, A is phenyl. In another embodiment, A is pyridyl,preferably 3-pyridyl. In another embodiment, A is thiazolyl, preferably5-thiazolyl. In one embodiment, A has 0, 1 or 2 substituents R¹. In afurther embodiment, A has 0 or 1 substituent R¹. In a furtherembodiment, A has 0 substituent R¹. In a further embodiment, A has 1 or2 substituents R¹. In a further embodiment, A has 1 substituent R¹. Inthe aforementioned embodiments, in which A has 0, 1 or 2 substituentsR¹, the total number of substituents R¹ is defined, including thepossibility that B may be R¹. Accordingly, if A has 0 substituents R¹,then B is not R¹.

In a compound of formula I, Ia, Ia-1, Ib or Ic, B is hydrogen, R¹ or-L-E. In one embodiment, B is -L-E. In a preferred embodiment, B ishydrogen or R¹. In a further preferred embodiment, B is hydrogen. Inanother embodiment, B is R¹.

In a compound of formula I, Ia, Ia-1, Ib or Ic, E is aryl or heteroaryl,wherein said aryl or said heteroaryl is optionally substituted with oneor more R². In one embodiment, E is an aryl group (e.g., phenyl,naphthyl or anthracenyl) optionally substituted with one or more R². Inanother embodiment, E is a heteroaryl group (e.g., pyridinyl,thiophenyl, pyrrolyl, furanyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, triazinyl, pyridazinyl, pyrazinyl,pyrimidinyl, quinolyl, indolyl, pyrazolyl, indazolyl, imidazolyl orbenzimidazolyl) optionally substituted with one or more R². Preferably,E is monocyclic aryl (i.e. phenyl) or monocyclic heteroaryl, whereinsaid monocyclic aryl or said monocyclic heteroaryl is optionallysubstituted with one or more R². In one embodiment, E has 0, 1, 2 or 3substituents R². In another embodiment, E has 0, 1 or 2 substituents R².In another embodiment, E has 0 or 1 substituents R². In anotherembodiment, E has 0 substituents R². In another embodiment, E has 1substituent R². Preferably, E is phenyl optionally substituted with oneor more R². In one embodiment, E is phenyl optionally substituted withone, two or three R². In another embodiment, E is phenyl optionallysubstituted with one or two R². In a further embodiment, E is phenyloptionally substituted with one R². In another embodiment, E is phenyl.In another embodiment, E is phenyl substituted with one, two or three,preferably one or two, R². In another preferred embodiment, E isheteroaryl, preferably monocyclic heteroaryl, optionally substitutedwith one or more (preferably one, two or three) R². In one embodiment, Eis heteroaryl, preferably monocyclic heteroaryl. In another embodiment,E is heteroaryl (preferably monocyclic heteroaryl) substituted with one,two or three, preferably one or two, R².

In a compound of formula I, Ia, Ia-1, Ib or Ic, L is a bond, —O—, —NH—,—N(C₁₋₄ alkyl)-, C₁₋₄ alkylene or heteroC₁₋₄ alkylene. Preferably saidheteroC₁₋₄ alkylene is —(CH₂)_(x)—NH— or —(CH₂)_(x)—O—, wherein x is 1,2, 3 or 4; still more preferably, said —(CH₂)_(x)—NH— or —(CH₂)_(x)—O—groups are linked to ring A through the N or O atom, respectively, andare linked to ring E through the —(CH₂)_(x)— group. More preferably,said heteroC₁₋₄ alkylene is —CH₂—NH— or —CH₂—O—, wherein said —CH₂—NH—and —CH₂—O— groups are linked to ring A through the N or O atom,respectively, and are linked to ring E through the —CH₂— group.

In one embodiment, L is a bond, —O—, —NH—, —N(C₁₋₄ alkyl)-, —CH₂—,CH₂—CH₂—, —CH₂—NH— or —CH₂—O—. In a preferred embodiment, L is a bond,—O—, —NH—, —N(C₁₋₄ alkyl)-, —CH₂—NH— or —CH₂—O—. In a more preferredembodiment, L is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—. In a stillmore preferred embodiment, L is a bond or —CH₂—O—. In a furtherpreferred embodiment, L is a bond. In another embodiment, L is —O—,—NH—, —N(C₁₋₄ alkyl)-, C₁₋₄ alkylene or heteroC₁₋₄ alkylene; preferably,L is —O—, —NH—, —N(C₁₋₄ alkyl)-, —CH₂—, CH₂—CH₂—, —CH₂—NH— or —CH₂—O—;more preferably L is —O—, —NH—, —N(C₁₋₄ alkyl)-, —CH₂—NH— or —CH₂—O—;even more preferably L is —O—, —NH—, —CH₂—NH—, or —CH₂—O—; still morepreferably L is —NH—, —CH₂—NH—, or —CH₂—O—; and particularly preferablyL is —CH₂—O—. Preferably, in all these embodiments, said —CH₂—NH— or—CH₂—O— groups are linked to ring A through the N or O atom,respectively, and are linked to ring E through the —CH₂— group.

In one embodiment, B is -L-E; E is aryl or heteroaryl, wherein said arylor said heteroaryl is optionally substituted with one or more R²; and Lis a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—, wherein the groups —CH₂—NH—and —CH₂—O— are linked to ring A through the N or O atom, respectively,and are linked to ring E through the —CH₂— group. In another embodiment,B is -L-E; E is phenyl optionally substituted with one or more R²; and Lis a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—, wherein the groups —CH₂—NH—and —CH₂—O— are linked to ring A through the N or O atom, respectively,and are linked to ring E through the —CH₂— group. In another embodiment,B is -L-E; E is aryl or heteroaryl, wherein said aryl or said heteroarylis optionally substituted with one or more R²; and L is a bond or—CH₂—O—, wherein the group —CH₂—O— is linked to ring A through the Oatom and to ring E through the —CH₂— group. In another embodiment, B is-L-E; E is phenyl optionally substituted with one or more R²; and L is abond or —CH₂—O—, wherein the group —CH₂—O— is linked to ring A throughthe O atom and to ring E through the —CH₂— group. In another embodiment,B is -L-E; E is aryl or heteroaryl, wherein said aryl or said heteroarylis optionally substituted with one or more R²; and L is a bond. Inanother embodiment, B is -L-E; E is phenyl optionally substituted withone or more R²; and L is a bond. In another embodiment, B is -L-E; E isheteroaryl optionally substituted with one or more R²; and L is a bond.In another embodiment, B is -L-E; E is aryl or heteroaryl; and L is abond. In another embodiment, B is -L-E; E is aryl or heteroaryl, whereinsaid aryl or said heteroaryl is optionally substituted with one or moreR²; and L is —CH₂—O—, wherein the group —CH₂—O— is linked to ring Athrough the O atom and to ring E through the —CH₂— group. In anotherembodiment, B is -L-E; E is phenyl optionally substituted with one ormore R²; and L is —CH₂—O—, wherein the group —CH₂—O— is linked to ring Athrough the O atom and to ring E through the —CH₂— group. In anotherembodiment, B is -L-E; E is heteroaryl (preferably monocyclicheteroaryl, more preferably pyridinyl), wherein said heteroaryl isoptionally substituted with one or more R²; and L is —CH₂—O—, whereinthe group —CH₂—O— is linked to ring A through the O atom and to ring Ethrough the —CH₂— group. In another embodiment, B is -L-E; E is aryl orheteroaryl, wherein said aryl or said heteroaryl is optionallysubstituted with one or more R²; and L is —O—, —NH—, —N(C₁ alkyl)-, C₁₋₄alkylene, or —CH₂—NH—, and more preferably L is —O—, —NH— or —CH₂—NH—wherein the group —CH₂—NH— is linked to ring A through the N atom and toring E through the —CH₂— group. In another embodiment, B is -L-E; E isaryl or heteroaryl, wherein said aryl or said heteroaryl is optionallysubstituted with one or more R²; and L is —NH— or —CH₂—NH—, wherein thegroup —CH₂—NH— is linked to ring A through the N atom and to ring Ethrough the —CH₂— group.

In a compound of formula I, Ia, Ia-1, Ib or Ic, each R¹ is independentlyselected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, cyclyl, amino,amido, hydroxyl, nitro, halo, haloC₁₋₈ alkyl, haloC₁₋₈ alkoxy, cyano,sulfinyl, sulfonyl, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, O-carboxy,C-carboxy, carbamate and urea. When there is more than one R¹ as asubstituent on ring A, they can be the same or different. In oneembodiment, each R¹ is independently selected from C₁₋₈ alkyl, cyclyl,amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈ alkoxy, cyano,sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, and urea. Inanother embodiment, each R¹ is independently selected from C₁₋₈ alkyl,amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈ alkoxy, cyano,sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, and urea. Inanother embodiment, each R¹ is independently selected from C₁₋₈ alkyl,amino, amido, halo, haloC₁₋₈ alkyl, haloC₁₋₈ alkoxy, cyano, sulfonamide,C₁₋₈ alkoxy, acyl, carboxyl, carbamate, and urea. In another embodiment,each R¹ is independently selected from halo, C₁₋₄ alkyl (e.g. methyl),haloC₁₋₄ alkyl (e.g. trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) andC₃₋₆ cycloalkyl (e.g. cyclopropyl), preferably each R¹ is independentlyselected from halo, C₁₋₄ alkyl (e.g. methyl) and C₁₋₄ alkoxy (e.g.methoxy). In another embodiment, each R¹ is independently selected fromhalo, C₁₋₄ alkyl and C₃₋₆ cycloalkyl.

In a compound of formula I, Ia, Ia-1, Ib or Ic, each R² is independentlyselected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, cyclyl, amino,amido, hydroxyl, nitro, halo, haloC₁₋₈ alkyl, haloC₁₋₈ alkoxy, cyano,sulfinyl, sulfonyl, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, O-carboxy,C-carboxy, carbamate and urea. When there is more than one R² as asubstituent on ring E, they can be the same or different. In oneembodiment, each R² is independently selected from C₁₋₈ alkyl, cyclyl,hydroxyl, halo, haloC₁₋₈a alkyl, haloC₁₋₈ alkoxy, cyano, sulfonamide andC₁₋₈ alkoxy. Preferably, each R² is independently selected from C₁₋₈alkyl, cyclyl, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈ alkoxy, cyano,N-sulfonamido and C₁₋₈ alkoxy; more preferably each R² is independentlyselected from C₁₋₈ alkyl, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, N-sulfonamido and C₁₋₈ alkoxy. In another embodiment,each R² is independently selected from hydroxyl, halo (for examplefluoro or chloro), haloC₁₋₈ alkyl (for example trifluoromethyl) andsulfonamide (preferably N-sulfonamido). In another embodiment, each R²is independently selected from hydroxyl, halo, haloC₁₋₈ alkyl andN-sulfonamido. In another embodiment, each R² is independently selectedfrom hydroxyl, halo, haloC₁₋₈ alkyl and —NR′SO₂R (wherein R and R′ areas defined herein below; preferably R′ is H and R is C₁₋₈ alkyl (forexample, methyl, ethyl or isopropyl) or R′ is H and R is optionallysubstituted phenyl). In another embodiment, each R² is independentlyselected from hydroxyl, halo, haloC₁₋₈ alkyl and —NHSO₂R (wherein R isC₁₋₈ alkyl (for example, methyl, ethyl or isopropyl), optionallysubstituted phenyl (for example phenyl, 2-cyanophenyl, 3-cyanophenyl,4-cyanophenyl, 2-aminophenyl, 3-aminophenyl or 4-aminophenyl),optionally substituted heterocycloalkyl (for example piperazin-1-yl), oroptionally substituted heteroaryl (for example 3-pyridyl or6-amino-3-pyridyl)). In another embodiment, each R² is independentlyselected from hydroxyl, halo and haloC₁₋₈ alkyl. In another embodiment,each R² is independently selected from hydroxyl, halo and haloC₁₋₄alkyl. In another embodiment, each R² is independently selected fromhydroxyl, chloro, fluoro or trifluoromethyl. In a further embodiment,ring E is substituted with one R² and said R² is —NHSO₂R, wherein R isC₁₋₈ alkyl (for example, methyl, ethyl or isopropyl), optionallysubstituted phenyl (for example phenyl or 2-cyanophenyl), optionallysubstituted heterocycloalkyl (for example piperazin-1-yl), or optionallysubstituted heteroaryl (for example 3-pyridyl or 6-amino-3-pyridyl).

In a compound of formula I, Ia, Ia-1, Ib or Ic, D is a cycloalkyl grouphaving from 4 to 7 C atoms, wherein said cycloalkyl group has one or twosubstituents R³ and is further optionally substituted with one or moreR⁴, and wherein the cycloalkyl group optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group (i.e. forming a bridged structure), wherein p        is 1 or 2 and each R^(a) independently is hydrogen or C₁₋₄        alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group via a single carbon        atom common to both rings (i.e. forming a spiro cycle), and        wherein said second ring is optionally substituted with one or        more R⁶.

The cycloalkyl group in D is thus always substituted with either one ortwo groups R³, which can be the same or different and can be placed onany available position of the cycloalkyl group, preferably on differentring C atoms, but preferably not on the ring C atom linking saidcycloalkyl group to the rest of the molecule. Preferably, the R³ group(or one of the two R³ groups, if two R³ groups are present) is placed atthe most opposed C atom to the C atom linking the cycloalkyl group tothe remainder of the compound of formula I, this meaning a “1,4”-like or“para”-like disposition for cyclobutyl and cyclohexyl rings and a“1,3”-like or “meta”-like disposition for cyclopentyl and cycloheptylrings. In a preferred embodiment, there is only one R³ group on thecycloalkyl group. Said cycloalkyl group may have one or more furtheradditional substitutents R⁴, which can be the same or different and maybe placed at any available position of the cycloalkyl group.Additionally, the cycloalkyl group can be fused to a second ring, orform bridged or spiro structures, as defined in more detail above.

In one embodiment, D is a cycloalkyl group having from 4 to 7 C atoms,preferably a cyclohexyl group, wherein said cycloalkyl group (preferablycyclohexyl) has one or two substituents R³ and is further optionallysubstituted with one or more R⁴, and wherein the cycloalkyl group(preferably, cyclohexyl) is optionally fused to a phenyl or a 5- or6-membered aromatic heterocyclic ring containing from 1 to 3 heteroatomsindependently selected from N, O and S, wherein said fused phenyl orsaid fused aromatic heterocyclic ring is optionally substituted with oneor more R⁵.

In a preferred embodiment, D is a cycloalkyl group having from 4 to 7 Catoms, preferably a cyclohexyl group, wherein said cycloalkyl group(preferably, cyclohexyl) has one or two substituents R³ and is furtheroptionally substituted with one or more R⁴.

In a more preferred embodiment, D is a cycloalkyl group having from 4 to7 C atoms, preferably a cyclohexyl group, wherein said cycloalkyl group(preferably cyclohexyl) has one substituent R³ and is further optionallysubstituted with one or more R⁴.

In a still more preferred embodiment, D is a cycloalkyl group havingfrom 4 to 7 C atoms, preferably a cyclohexyl group, wherein saidcycloalkyl group (preferably cyclohexyl) has one substituent R³.

In another embodiment, D is a cycloalkyl group having from 4 to 7 Catoms, preferably a cyclohexyl group, wherein said cycloalkyl group(preferably cyclohexyl) has one or two substituents R³ and is furtheroptionally substituted with one or more R⁴, and wherein the cycloalkylgroup (preferably cyclohexyl) is fused to a phenyl or a 5- or 6-memberedaromatic heterocyclic ring containing from 1 to 3 heteroatomsindependently selected from N, O and S, wherein said fused phenyl orsaid fused aromatic heterocyclic ring is optionally substituted with oneor more R⁵.

In another embodiment, D is a cycloalkyl group having from 4 to 7 Catoms, preferably a cyclohexyl group, wherein said cycloalkyl group hasone or two substituents R³ and is further optionally substituted withone or more R⁴, and wherein the cycloalkyl group is bonded to a linkergroup —(C(R^(a))₂)_(p)— linking together any two non-adjacent ringcarbon atoms of the cycloalkyl group, wherein p is 1 or 2 and each R^(a)independently is hydrogen or C₁₋₄ alkyl.

In another embodiment, D is a cycloalkyl group having from 4 to 7 Catoms, preferably a cyclohexyl group, wherein said cycloalkyl group hasone or two substituents R³ and is further optionally substituted withone or more R⁴, and wherein the cycloalkyl group is linked to a secondring that is either a 3- to 7-membered saturated carbocyclic ring or a3- to 7-membered saturated heterocyclic ring containing from 1 to 3heteroatoms independently selected from N, O and S, wherein said secondring is linked together with the cycloalkyl group via a single carbonatom common to both rings, and wherein said second ring is optionallysubstituted with one or more R⁶.

In a preferred embodiment, D is selected from D1, D2, D3 and D4:

wherein the cyclobutyl ring comprised in D1, the cyclopentyl ringcomprised in D2, the cyclohexyl ring comprised in D3 and the cycloheptylring comprised in D4 is optionally substituted with one further R³ andis optionally substituted with one or more R⁴, wherein the cyclobutylring comprised in D1 optionally:

-   -   (a) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cyclobutyl ring comprised in D1, wherein p is 1 or 2 and each        R^(a) independently is hydrogen or C₁₋₄ alkyl; or    -   (b) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cyclobutyl ring comprised in D1 via        a single carbon atom common to both rings, and wherein said        second ring is optionally substituted with one or more R⁶;        and wherein the cyclopentyl ring comprised in D2, the cyclohexyl        ring comprised in D3 and the cycloheptyl ring comprised in D4        optionally:    -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group (i.e., of the cyclopentyl ring comprised in D2,        the cyclohexyl ring comprised in D3 or the cycloheptyl ring        comprised in D4), wherein p is 1 or 2 and each R^(a)        independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group (i.e., with the        cyclopentyl ring comprised in D2, the cyclohexyl ring comprised        in D3 or the cycloheptyl ring comprised in D4) via a single        carbon atom common to both rings, and wherein said second ring        is optionally substituted with one or more R⁶.

It is to be understood that the bond to the opposite of R³ shown in theabove formulae D1, D2, D3 and D4 denotes the point of attachment of therespective group D1, D2, D3 or D4 to the remainder of the compound ofFormula I, Ia, Ia-1, Ib or Ic.

In another preferred embodiment, D is selected from D1, D2, D3 and D4:

wherein the cyclobutyl ring comprised in D1, the cyclopentyl ringcomprised in D2, the cyclohexyl ring comprised in D3 and the cycloheptylring comprised in D4 is optionally substituted with one further R³ andis optionally substituted with one or more R⁴.

In another preferred embodiment, D is selected from D1, D2, D3 and D4:

wherein the cyclobutyl ring comprised in D1, the cyclopentyl ringcomprised in D2, the cyclohexyl ring comprised in D3 and the cycloheptylring comprised in D4 is optionally substituted with one or more R⁴.

In a more preferred embodiment, D is

wherein the cyclohexyl ring comprised in D is optionally substitutedwith one further R³ and is optionally substituted with one or more R⁴,and wherein the cyclohexyl ring comprised in D optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group (i.e., the cyclohexyl ring), wherein p is 1 or        2 and each R^(a) independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group (i.e., the        cyclohexyl ring) via a single carbon atom common to both rings,        and wherein said second ring is optionally substituted with one        or more R⁶.

In a still more preferred embodiment, D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group (i.e., the cyclohexyl ring), wherein p is 1 or        2 and each R^(a) independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group (i.e., the        cyclohexyl ring) via a single carbon atom common to both rings,        and wherein said second ring is optionally substituted with one        or more R⁶.

In an even more preferred embodiment, D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴.

In a particularly preferred embodiment, D is

In another embodiment, D is a group of formula

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴.

In another embodiment, D is a group of formula

In a compound of formula I, Ia, Ia-1, Ib or Ic, each R³ is independentlyselected from —NR⁷R⁸, —NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰,—NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —OH, —CONR⁷R⁸, oxo, —C₁₋₄ alkylene-NR⁷R⁸,—C₁₋₄ alkylene-NHOH, —C₁₋₄ alkyene-NR⁹COR¹⁰, —C₁₋₄ alkylene-NR⁹SO₂R¹⁰,—C₁₋₄ alkylene-NR⁹COOR¹⁰, —C₁₋₄ alkylene-NR⁹CONR⁷R⁸, —C₁₋₄alkylene-NR⁹SO₂NR⁷R⁸, —C₁₋₄ alkylene-OH and —C₁₋₄ alkylene-CONR⁷R⁸. WhenR³ is oxo (i.e. a group of formula ═O), then there can be no furthersubstituent (either R³, if a second R³ is present, or R⁴) in thatposition, i.e. on the C atom on which the oxo group is placed. It isfurther to be understood that, if R³ in any of the above formulae D1,D2, D3 or D4 is oxo (i.e., ═O), then this oxo group is bound to therespective cycloalkyl ring through a carbon-to-carbon double bond. In apreferred embodiment, there is only one R³ on a compound of formula I,Ia, Ia-1, Ib or Ic.

In one embodiment, each R³ is independently selected from —NR⁷R⁸, —NHOH,—NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —CONR⁷R⁸,oxo, —C₁₋₄ alkylene-NR⁷R⁸, —C₁₋₄ alkylene-NHOH, —C₁₋₄ alkyene-NR⁹COR¹⁰,—C₁₋₄ alkylene-NR⁹SO₂R¹⁰, —C₁₋₄ alkylene-NR⁹COOR¹⁰, —C₁₋₄alkylene-NR⁹CONR⁷R⁸, —C₁₋₄ alkylene-NR⁹SO₂NR⁷R⁸, —C₁₋₄ alkylene-OH and—C₁₋₄ alkylene-CONR⁷R⁸. In a preferred embodiment, there is only one R³.

In another embodiment, each R³ is independently selected from —NR⁷R⁸,—NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R⁰, —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —OH,oxo, —C₁₋₄ alkylene-NR⁷R⁸, —C₁₋₄ alkylene-NHOH, —C₁₋₄ alkyene-NR⁹COR¹⁰,—C₁₋₄ alkylene-NR⁹SO₂R¹⁰, —C₁₋₄ alkylene-NR⁹COOR¹⁰, —C₁₋₄alkylene-NR⁹CONR⁷R⁸, —C₁₋₄ alkylene-NR⁹SO₂NR⁷R⁸, and —C₁₋₄ alkylene-OH.In a preferred embodiment, there is only one R³.

In another embodiment, each R³ is independently selected from —NR⁷R⁸,—NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸,oxo, —C₁₋₄ alkylene-NR⁷R⁸, —C₁₋₄ alkylene-NHOH, —C₁₋₄ alkyene-NR⁹COR¹⁰,—C₁₋₄ alkylene-NR⁹SO₂R¹⁰, —C₁₋₄ alkylene-NR⁹COOR¹⁰, —C₁₋₄alkylene-NR⁹CONR⁷R⁸, —C₁₋₄ alkylene-NR⁹SO₂NR⁷R⁸, and —C₁₋₄ alkylene-OH.In a preferred embodiment, there is only one R³.

In another embodiment, each R³ is independently selected from —NR⁷R⁸,—NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸,—OH, —CONR⁷R⁸, and oxo. In a preferred embodiment, there is only one R³.

In another embodiment, each R³ is independently selected from —NR⁷R⁸,—NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸,—CONR⁷R⁸, and oxo. In a preferred embodiment, there is only one R³.

In another embodiment, each R³ is independently selected from —NR⁷R⁸,—NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸,—OH, and oxo. In a preferred embodiment, there is only one R³.

In another embodiment, each R³ is independently selected from —NR⁷R⁸,—NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R⁰, —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, andoxo. In a preferred embodiment, there is only one R³.

In another embodiment, each R³ is independently selected from —NR⁷R⁸,—NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸, —OH, —CONR⁷R⁸, and oxo.In a preferred embodiment, there is only one R³.

In another embodiment, each R³ is independently selected from —NR⁷R⁸,—NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸, —CONR⁷R⁸, and oxo. In apreferred embodiment, there is only one R³.

In another embodiment, each R³ is independently selected from —NR⁷R⁸,—NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR⁰O, —NR⁹CONR⁷R⁸, —OH, and oxo. In apreferred embodiment, there is only one R³.

In another embodiment, each R³ is independently selected from —NR⁷R⁸,—NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸, and oxo. In a preferredembodiment, there is only one R³.

In another embodiment, each R³ is independently selected from —NR⁷R⁸,—NR⁹COR¹⁰, —NR⁹SO₂R⁰, —OH, and oxo. In a preferred embodiment, there isonly one R³.

In another embodiment, each R³ is independently selected from —NR⁷R⁸,—NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, and oxo. In a preferred embodiment, there is onlyone R³.

In another embodiment, each R³ is independently selected from —NR⁷R⁸,—OH, oxo, —C₁₋₄ alkylene-NR⁷R⁸, and —C₁₋₄ alkylene-OH. In a preferredembodiment, there is only one R³.

In another embodiment, each R³ is independently selected from —NR⁷R⁸,oxo, —C₁₋₄ alkylene-NR⁷R⁸, and —C₁₋₄ alkylene-OH. In a preferredembodiment, there is only one R³.

In another embodiment, each R³ is independently selected from —NR⁷R⁸,—OH and oxo. In a preferred embodiment, there is only one R³.

In another embodiment, each R³ is independently selected from —NR⁷R⁸,and —OH. In a preferred embodiment, there is only one R³.

In a preferred embodiment, each R³ is independently selected from —NR⁷R⁸and —C₁₋₄ alkylene-NR⁷R⁸. Preferably, said —C₁₋₄ alkylene-NR⁷R⁸ is —C₁₋₂alkylene-NR⁷R⁸. In a preferred embodiment, there is only one R³.

In a more preferred embodiment, each R³ is independently selected from—NR⁷R⁸. In a preferred embodiment, there is only one R³.

In a compound of formula I, Ia, Ia-1, Ib or Ic, each R⁴ and each R⁶ isindependently selected from C₁₋₈ alkyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy and C₁₋₈ alkoxy. Preferably, each R⁴ and each R⁶ is independentlyselected from C₁₋₈ alkyl, halo and Cl-s alkoxy. More preferably, each R⁴and each R⁶ is independently selected from C₁₋₄ alkyl, halo and C₁₋₄alkoxy.

In a compound of formula I, Ia, Ia-1, Ib or Ic, each R⁷ and each R⁸ isindependently selected from hydrogen, C₁₋₈ alkyl, R¹²R¹³N—C₁₋₈ alkyl andhydroxyC₁₋₈ alkyl, or R⁷ and R⁸ are linked together to form, along withthe N atom to which they are bound, a saturated 3- to 7-memberedheterocyclic ring which optionally contains one further heteroatomselected from N, O and S, wherein one or more C atoms in saidheterocyclic ring are optionally oxidized to form CO groups, wherein oneor more S atoms in said heterocyclic ring, if present, are optionallyoxidized to form independently SO groups or SO₂ groups, and wherein saidheterocyclic ring is optionally substituted with one or more R¹¹.Preferably, the alkyl groups indicated above, either as a group or partof a group (e.g. in an R¹²R¹³N—C₁₋₈ alkyl or hydroxyC₁₋₈ alkyl group),are C₁₋₄ alkyl, more preferably C₁₋₂ alkyl. In one embodiment, each R⁷and each R⁸ is independently selected from hydrogen, C₁₋₈ alkyl,R¹²R¹³N—C₁₋₈ alkyl (preferably H₂N—C₁₋₈ alkyl) and hydroxyC₁₋₄ alkyl;preferably, each R⁷ and each R⁸ is independently selected from hydrogen,C₁₋₄ alkyl, R¹²R¹³N—C₁₋₄ alkyl (preferably H₂N—C₁₋₄ alkyl) andhydroxyC₁₋₄ alkyl, and more preferably each R⁷ and each R⁸ isindependently selected from hydrogen, C₁₋₂ alkyl, R¹²R¹³N—C₁₋₂ alkyl(preferably H₂N—C₁₋₂ alkyl) and hydroxyC₁₋₂ alkyl. In a preferredembodiment, R⁷ and R⁸ are each hydrogen.

In another embodiment, R⁷ and R⁸ are linked together to form, along withthe N atom to which they are bound, a saturated 3- to 7-memberedheterocyclic ring which optionally contains one further heteroatomselected from N, O and S, wherein one or more C atoms in saidheterocyclic ring are optionally oxidized to form CO groups, wherein oneor more S atoms in said heterocyclic ring, if present, are optionallyoxidized to form independently SO groups or SO₂ groups, and wherein saidheterocyclic ring is optionally substituted with one or more R¹¹. In onespecific embodiment, —NR⁷R⁸ is a group of formula:

In a compound of formula I, Ia, Ia-1, Ib or Ic, each R⁹ is independentlyselected from hydrogen and C₁₋₄ alkyl. In a preferred embodiment, eachR⁹ is hydrogen.

In a compound of formula I, Ia, Ia-1, Ib or Ic, each R¹⁰ isindependently selected from C₁₋₈ alkyl, haloC₁₋₈ alkyl, cyclyl andcyclylC₁₋₈ alkyl, wherein said cyclyl or the cyclyl moiety comprised insaid cyclylC₁₋₈ alkyl (i.e., any of the aforementioned cyclyl groups,including also the cyclyl group forming part of the cyclylC₁₋₈ alkylgroup) is optionally substituted with one or more R¹⁴. In oneembodiment, each R¹⁰ is selected from C₁₋₈ alkyl and cyclyl optionallysubstituted with one or more R¹⁴, preferably each R¹⁰ is selected fromC₁₋₄ alkyl (e.g. methyl) and aryl (preferably phenyl) optionallysubstituted with one or more R¹⁴. In another embodiment, each R¹⁰ isC₁₋₈ alkyl, for example C₁₋₄ alkyl. In another embodiment, each R¹⁰ iscyclyl optionally substituted with one or more R¹⁴, for example aryloptionally substituted with one or more R¹⁴, preferably phenyloptionally substituted with one or more R¹⁴. The aforementioned groupsoptionally substituted with one or more R¹⁴ may, e.g., be substitutedwith one, two or three R¹⁴.

In another embodiment there is one R³ and said R³ is selected from—NR⁷R⁸ and —C₁₋₄ alkylene-NR⁷R⁸, wherein the moiety —NR⁷R⁸ in —NR⁷R⁸ andin —C₁₋₄ alkylene-NR⁷R⁸ is —NH₂ or a group of formula:

In a specific aspect of the above embodiment, there is one R³ and saidR³ is selected from —NH₂ and —C₁₋₄ alkylene-NH₂, preferably from —NH₂and —C₁₋₂ alkylene-NH₂ (e.g. —CH₂—NH₂, —CH₂—CH₂—NH₂ or —CH(CH₃)—NH₂).

In another embodiment there is one R³ and said R³ is —NR⁷R⁸, wherein—NR⁷R⁸ is —NH₂ or a group of formula:

In another embodiment there is one R³ and said R³ is —NH₂.

In another embodiment there is one R³ and said R³ is a group of formula:

In the above embodiments as well as in all the embodiments of thecompounds of the invention described below, the following compounds areexcluded:

-   2-((2-phenylcyclopropyl)amino)cycloheptanol, and-   2-((2-phenylcyclopropyl)amino)cyclopentanol.

Preferably, in the above embodiments as well as in all the embodimentsof the compounds of the invention described below also the compound2-((2-phenylcyclopropyl)amino)cyclohexanol is excluded.

The substituents of the cyclopropyl moiety -A-B and —NH-D in a compoundof formula I, Ia, Ib or Ic are preferably in the trans-configuration.Thus, in one embodiment, the invention provides a compound of formula I(including a compound Ia, Ib or Ic) wherein the groups -A-B and —NH-Dare in trans configuration. In a preferred embodiment, the inventionprovides a compound of formula Ia wherein the groups -A-B and —NH-D arein trans configuration, which is a compound of formula Ia-1:

wherein the groups and variables of formula Ia-1, including A, B, D, E,L, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴, areas defined above in relation to a compound of formula I and Ia and inthe various preferred embodiments for a compound of formula I and Iadescribed above. The above chemical representation for a compound offormula Ia-1 does not intend to indicate absolute stereochemistry of thetwo chiral centers on the cyclopropyl ring, but only their relativestereochemistry (which is trans). Thus a compound of formula Ia-1therefore relates to individual optically active trans isomers as wellas mixtures of trans-isomers.

In one embodiment, the invention provides a compound of formula Iwherein each R^(w), R^(x), R^(y) and R^(z) is independently selectedfrom hydrogen, fluoro and C₁₋₄ alkyl, preferably from hydrogen, fluoroand methyl.

In another embodiment, the invention provides a compound of formula Iwherein each R^(w), R^(x), R^(y) and R^(z) is independently selectedfrom hydrogen and fluoro.

In another embodiment, the invention provides a compound of formula Iwherein R^(w) is fluoro and each R^(x), R^(y) and R^(z) is independentlyselected from hydrogen, halo and C₁₋₄ alkyl; preferably, R^(w) is fluoroand each R^(x), R^(y) and R^(z) is hydrogen.

In another embodiment, the invention provides a compound of formula Iwherein R^(z) is fluoro and each R^(w), R^(x) and R^(y) is independentlyselected from hydrogen, halo and C₁₋₄ alkyl; preferably, R^(z) is fluoroand each R^(w), R^(x) and R^(y) is hydrogen.

In another embodiment, the invention provides a compound of formula Iwherein R^(w) and R^(z) are fluoro and each R^(x) and R^(y) isindependently selected from hydrogen, halo and C₁₋₄ alkyl; preferably,R^(w) and R^(z) are fluoro and each R^(x) and R^(y) is hydrogen.

In a preferred embodiment, the invention provides a compound of formulaI wherein R^(w) is selected from hydrogen, halo and C₁₋₄ alkyl,preferably from hydrogen, fluoro and methyl, and each R^(x), R^(y) andR^(z) is hydrogen.

In a more preferred embodiment, the invention provides a compound offormula I wherein each R^(w), R^(x), R^(y) and R^(z) is hydrogen, i.e. acompound of formula Ia:

In another embodiment, the invention provides a compound of formula Iwherein each R^(w), R^(x), R^(y) and R^(z) is independently selectedfrom hydrogen, halo and C₁₋₄ alkyl with the proviso that at least one isnot hydrogen, i.e. a compound of formula Ib.

In another embodiment, the invention provides a compound of formula Iwherein R^(w) is selected from halo and C₁₋₄ alkyl, preferably fromfluoro and methyl, and each R^(x), R^(y) and R^(z) is hydrogen, i.e. acompound of formula Ic. Preferably, in a compound of formula Ic R^(w) ismethyl.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein D is selected from D1, D2, D3 and D4:

wherein the cyclobutyl ring comprised in D1, the cyclopentyl ringcomprised in D2, the cyclohexyl ring comprised in D3 and the cycloheptylring comprised in D4 is optionally substituted with one further R³ andis optionally substituted with one or more R⁴, and wherein thecyclobutyl ring comprised in D1, the cyclopentyl ring comprised in D2,the cyclohexyl ring comprised in D3 and the cycloheptyl ring comprisedin D4 optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵ (option (a) applies only to D2,        D3 and D4 but not to D1); or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group (i.e., the cyclobutyl ring comprised in D1, the        cyclopentyl ring comprised in D2, the cyclohexyl ring comprised        in D3 or the cycloheptyl ring comprised in D4), wherein p is 1        or 2 and each R^(a) independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group (i.e., the        cyclobutyl ring comprised in D1, the cyclopentyl ring comprised        in D2, the cyclohexyl ring comprised in D3 or the cycloheptyl        ring comprised in D4) via a single carbon atom common to both        rings, and wherein said second ring is optionally substituted        with one or more R⁶.

In a preferred embodiment, the invention provides a compound of formulaI, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein D is

wherein the cyclohexyl ring comprised in D is optionally substitutedwith one further R³ and is optionally substituted with one or more R⁴,and wherein the cyclohexyl ring comprised in D optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group (i.e., the cyclohexyl ring), wherein p is 1 or        2 and each R^(a) independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group (i.e., the        cyclohexyl ring) via a single carbon atom common to both rings,        and wherein said second ring is optionally substituted with one        or more R⁶.

In another preferred embodiment, the invention provides a compound offormula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia,or Ia-1, more preferably a compound of formula Ia or Ia-1, and mostpreferably a compound of formula Ia-1) wherein D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group (i.e., the cyclohexyl ring), wherein p is 1 or        2 and each R^(a) independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group (i.e., the        cyclohexyl ring) via a single carbon atom common to both rings,        and wherein said second ring is optionally substituted with one        or more R⁶.

In a more preferred embodiment, the invention provides a compound offormula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia,or Ia-1, more preferably a compound of formula Ia or Ia-1, and mostpreferably a compound of formula Ia-1) wherein D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴.

In a still more preferred embodiment, the invention provides a compoundof formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I,Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and mostpreferably a compound of formula Ia-1) wherein D is

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein D is

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein each R³ is independently selected from—NR⁷R⁸, —NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸,—NR⁹SO₂NR⁷R⁸, oxo, —C₁₋₄ alkylene-NR⁷R⁸, —C₁₋₄ alkylene-NHOH, —C₁₋₄alkyene-NR⁹COR¹⁰, —C₁₋₄ alkylene-NR⁹SO₂R¹⁰, —C₁₋₄ alkylene-NR⁹COOR¹⁰,—C₁₋₄ alkylene-NR⁹CONR⁷R⁸, —C₁₋₄ alkylene- NR⁹SO₂NR⁷R⁸, and —C₁₋₄alkylene-OH.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein each R³ is independently selected from—NR⁷R⁸, —NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸,—NR⁹SO₂NR⁷R⁸, —OH, and oxo.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein each R³ is independently selected from—NR⁷R⁸, —NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸,—NR⁹SO₂NR⁷R⁸, and oxo.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein each R³ is independently selected from—NR⁷R⁸, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸, —OH, and oxo. Ina more specific embodiment, each R⁷ and each R⁸ is independentlyselected from hydrogen, C₁₋₈ alkyl, R¹²R¹³N—C₁₋₈ alkyl and hydroxyC₁₋₈alkyl; preferably, each R⁷ and each R⁸ is independently selected fromhydrogen, C₁₋₄ alkyl, R¹²R¹³N—C₁₋₄ alkyl and hydroxyC₁₋₄ alkyl, morepreferably each R⁷ and each R⁸ is independently selected from hydrogen,C₁₋₂ alkyl, R¹²R¹³N—C₁₋₂ alkyl and hydroxyC₁₋₂ alkyl, and even morepreferably R⁷ and R⁸ are each hydrogen; and each R¹⁰ is selected fromC₁₋₈ alkyl and cyclyl optionally substituted with one or more R¹⁴,preferably each R¹⁰ is selected from C₁₋₄ alkyl (e.g. methyl) and aryl(preferably phenyl) optionally substituted with one or more R¹⁴. Theaforementioned groups optionally substituted with one or more R¹⁴ may,e.g., be substituted with one, two or three R¹⁴.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein each R³ is independently selected from—NR⁷R⁸, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸, and oxo. In amore specific embodiment, each R⁷ and each R⁸ is independently selectedfrom hydrogen, C₁₋₈ alkyl, R¹²R¹³N—C₁₋₈ alkyl and hydroxyC₁₋₈ alkyl;preferably, each R⁷ and each R⁸ is independently selected from hydrogen,C₁₋₄ alkyl, R¹²R¹³N—C₁₋₄ alkyl and hydroxyC₁₋₄ alkyl, more preferablyeach R⁷ and each R⁸ is independently selected from hydrogen, C₁₋₂ alkyl,R¹²R¹³N—C₁₋₂ alkyl and hydroxyC₁₋₂ alkyl, and even more preferably R⁷and R⁸ are each hydrogen; and each R¹⁰ is selected from C₁₋₈ alkyl andcyclyl optionally substituted with one or more R¹⁴, preferably each R¹⁰is selected from C₁₋₄ alkyl (e.g. methyl) and aryl (preferably phenyl)optionally substituted with one or more R¹⁴. The aforementioned groupsoptionally substituted with one or more R¹⁴ may, e.g., be substitutedwith one, two or three R¹⁴.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein each R³ is independently selected from—NR⁷R⁸, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —OH, and oxo. In a more specificembodiment, each R⁷ and each R⁸ is independently selected from hydrogen,C₁₋₈ alkyl, R¹²R¹³N—C₁₋₈ alkyl and hydroxyC₁₋₈ alkyl; preferably, eachR⁷ and each R⁸ is independently selected from hydrogen, C₁₋₄ alkyl,R¹²R¹³N—C₁₋₄ alkyl and hydroxyC₁₋₄ alkyl, more preferably each R⁷ andeach R⁸ is independently selected from hydrogen, C₁₋₂ alkyl,R¹²R¹³N—C₁₋₂ alkyl and hydroxyC₁₋₂ alkyl, and even more preferably R⁷and R⁸ are each hydrogen; and each R¹⁰ is selected from C₁₋₈ alkyl andcyclyl optionally substituted with one or more R¹⁴, preferably each R¹⁰is selected from C₁₋₄ alkyl (e.g. methyl) and aryl (preferably phenyl)optionally substituted with one or more R¹⁴. The aforementioned groupsoptionally substituted with one or more R¹⁴ may, e.g., be substitutedwith one, two or three R¹⁴.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein each R³ is independently selected from—NR⁷R⁸, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, and oxo. In a more specific embodiment,each R⁷ and each R⁸ is independently selected from hydrogen, C₁₋₈ alkyl,R¹²R¹³N—C₁₋₈ alkyl and hydroxyC₁₋₈ alkyl; preferably, each R⁷ and eachR⁸ is independently selected from hydrogen, C₁₋₄ alkyl, R¹²R¹³N—C₁₋₄alkyl and hydroxyC₁₋₄ alkyl, more preferably each R⁷ and each R⁸ isindependently selected from hydrogen, C₁₋₂ alkyl, R¹²R¹³N—C₁₋₂ alkyl andhydroxyC₁₋₂ alkyl, and even more preferably R⁷ and R⁸ are each hydrogen;and each R¹⁰ is selected from C₁₋₈ alkyl and cyclyl optionallysubstituted with one or more R¹⁴, preferably each R¹⁰ is selected fromC₁₋₄ alkyl (e.g. methyl) and aryl (preferably phenyl) optionallysubstituted with one or more R¹⁴. The aforementioned groups optionallysubstituted with one or more R¹⁴ may, e.g., be substituted with one, twoor three R¹⁴.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein each R³ is independently selected from—NR⁷R⁸, —OH, oxo, —C₁₋₄ alkylene-NR⁷R⁸, and —C₁₋₄ alkylene-OH. In a morespecific embodiment each R⁷ and each R⁸ is independently selected fromhydrogen, C₁₋₈ alkyl, R¹²R¹³N—C₁₋₈ alkyl and hydroxyC₁₋₈ alkyl;preferably, each R⁷ and each R⁸ is independently selected from hydrogen,C₁₋₄ alkyl, R¹²R¹³N—C₁₋₄ alkyl and hydroxyC₁₋₄ alkyl, more preferablyeach R⁷ and each R⁸ is independently selected from hydrogen, C₁₋₂ alkyl,R¹²R¹³N—C₁₋₂ alkyl and hydroxyC₁₋₂ alkyl, and even more preferably R⁷and R⁸ are each hydrogen. In another specific embodiment, R⁷ and R⁸ arelinked together to form, along with the N atom to which they are bound,a saturated 3- to 7-membered heterocyclic ring which optionally containsone further heteroatom selected from N, O and S, wherein one or more Catoms in said heterocyclic ring are optionally oxidized to form COgroups, wherein one or more S atoms in said heterocyclic ring, ifpresent, are optionally oxidized to form independently SO groups or SO₂groups, and wherein said heterocyclic ring is optionally substitutedwith one or more (e.g., one, two or three) R¹, and preferably —NR⁷R⁸ isa group of formula:

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein each R³ is independently selected from—NR⁷R⁸, oxo, —C₁₋₄ alkylene-NR⁷R⁸, and —C₁₋₄ alkylene-OH. In a morespecific embodiment each R⁷ and each R⁸ is independently selected fromhydrogen, C₁₋₈ alkyl, R¹²R¹³N—C₁₋₈ alkyl and hydroxyC₁₋₈ alkyl;preferably, each R⁷ and each R⁸ is independently selected from hydrogen,C₁₋₄ alkyl, R¹²R¹³N—C₁₋₄ alkyl and hydroxyC₁₋₄ alkyl, more preferablyeach R⁷ and each R⁸ is independently selected from hydrogen, C₁₋₂ alkyl,R¹²R¹³N—C₁₋₂ alkyl and hydroxyC₁₋₂ alkyl, and even more preferably R⁷and R⁸ are each hydrogen. In another specific embodiment, R⁷ and R⁸ arelinked together to form, along with the N atom to which they are bound,a saturated 3- to 7-membered heterocyclic ring which optionally containsone further heteroatom selected from N, O and S, wherein one or more Catoms in said heterocyclic ring are optionally oxidized to form COgroups, wherein one or more S atoms in said heterocyclic ring, ifpresent, are optionally oxidized to form independently SO groups or SO₂groups, and wherein said heterocyclic ring is optionally substitutedwith one or more (e.g., one, two or three) R¹¹, and preferably —NR⁷R⁸ isa group of formula:

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein each R³ is independently selected from—NR⁷R⁸ and —OH. In a more specific embodiment each R⁷ and each R⁸ isindependently selected from hydrogen, C₁₋₈ alkyl, R¹²R¹³N—C₁₋₈ alkyl andhydroxyC₈a alkyl; preferably, each R⁷ and each R⁸ is independentlyselected from hydrogen, C₁₋₄ alkyl, R¹²R¹³N—C₁₋₄ alkyl and hydroxyC₁₋₄alkyl, more preferably each R⁷ and each R⁸ is independently selectedfrom hydrogen, C₁₋₂ alkyl, R¹²R¹³N—C₁₋₂ alkyl and hydroxyC₁₋₂ alkyl, andeven more preferably R⁷ and R⁸ are each hydrogen. In another specificembodiment, R⁷ and R⁸ are linked together to form, along with the N atomto which they are bound, a saturated 3- to 7-membered heterocyclic ringwhich optionally contains one further heteroatom selected from N, O andS, wherein one or more C atoms in said heterocyclic ring are optionallyoxidized to form CO groups, wherein one or more S atoms in saidheterocyclic ring, if present, are optionally oxidized to formindependently SO groups or SO₂ groups, and wherein said heterocyclicring is optionally substituted with one or more (e.g., one, two orthree) R¹¹, and preferably —NR⁷R⁸ is a group of formula:

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein each R³ is independently selected from—NR⁷R⁸ and —C₁₋₄ alkylene-NR⁷R⁸, preferably from —NR⁷R⁸ and —C₁₋₂alkylene-NR⁷R⁸. In a more specific embodiment each R⁷ and each R⁸ isindependently selected from hydrogen, C₁₋₈ alkyl, R¹²R¹³N—C₁₋₈ alkyl andhydroxyC₁₋₈ alkyl; preferably, each R⁷ and each R⁸ is independentlyselected from hydrogen, C₁₋₄ alkyl, R¹²R¹³N—C₁₋₄ alkyl and hydroxyC₁₋₄alkyl, more preferably each R⁷ and each R⁸ is independently selectedfrom hydrogen, C₁₋₂ alkyl, R¹²R¹³N—C₁₋₂ alkyl and hydroxyC₁₋₂ alkyl, andeven more preferably R⁷ and R⁸ are each hydrogen. In another specificembodiment, R⁷ and R⁸ are linked together to form, along with the N atomto which they are bound, a saturated 3- to 7-membered heterocyclic ringwhich optionally contains one further heteroatom selected from N, O andS, wherein one or more C atoms in said heterocyclic ring are optionallyoxidized to form CO groups, wherein one or more S atoms in saidheterocyclic ring, if present, are optionally oxidized to formindependently SO groups or SO₂ groups, and wherein said heterocyclicring is optionally substituted with one or more (e.g., one, two orthree) R¹¹, and preferably —NR⁷R⁸ is a group of formula:

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein each R³ is independently selected from—NR⁷R⁸. In a more specific embodiment each R⁷ and each R⁸ isindependently selected from hydrogen, C₁₋₈ alkyl, R¹²R¹³N—C₁₋₈ alkyl andhydroxyC₁₋₈ alkyl; preferably, each R⁷ and each R⁸ is independentlyselected from hydrogen, C₁₋₄ alkyl, R¹²R¹³N—C₁₋₄ alkyl and hydroxyC₁₋₄alkyl, more preferably each R⁷ and each R⁸ is independently selectedfrom hydrogen, C₁₋₂ alkyl, R¹²R¹³N—C₁₋₂ alkyl and hydroxyC₁₋₂ alkyl, andeven more preferably R⁷ and R⁸ are each hydrogen. In another specificembodiment, R⁷ and R⁸ are linked together to form, along with the N atomto which they are bound, a saturated 3- to 7-membered heterocyclic ringwhich optionally contains one further heteroatom selected from N, O andS, wherein one or more C atoms in said heterocyclic ring are optionallyoxidized to form CO groups, wherein one or more S atoms in saidheterocyclic ring, if present, are optionally oxidized to formindependently SO groups or SO₂ groups, and wherein said heterocyclicring is optionally substituted with one or more (e.g., one, two orthree) R¹¹, and preferably —NR⁷R⁸ is a group of formula:

In a preferred embodiment, the invention provides a compound of formulaI, Ia, Ia-1, Ib or Ic, including a compound I, Ia, Ia-1, Ib or Ic asdefined in the specific embodiments disclosed herein, wherein there isonly one substituent R³ on ring D.

In one embodiment, the invention provides a compound of formula I, Ia,Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, morepreferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is selected from D1, D2, D3 and D4:

wherein the cyclobutyl ring comprised in D1, the cyclopentyl ringcomprised in D2, the cyclohexyl ring comprised in D3 and the cycloheptylring comprised in D4 is optionally substituted with one further R³ andis optionally substituted with one or more R⁴, and wherein thecyclobutyl ring comprised in D1, the cyclopentyl ring comprised in D2,the cyclohexyl ring comprised in D3 and the cycloheptyl ring comprisedin D4 optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵ (option (a) applies only to D2,        D3 and D4 but not to D1); or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group (i.e., the cyclobutyl ring comprised in D1, the        cyclopentyl ring comprised in D2, the cyclohexyl ring comprised        in D3 or the cycloheptyl ring comprised in D4), wherein p is 1        or 2 and each R^(a) independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group (i.e., the        cyclobutyl ring comprised in D1, the cyclopentyl ring comprised        in D2, the cyclohexyl ring comprised in D3 or the cycloheptyl        ring comprised in D4) via a single carbon atom common to both        rings, and wherein said second ring is optionally substituted        with one or more R⁶; and        each R³ is independently selected from —NR⁷R⁸, —NHOH, —NR⁹COR¹⁰,        —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —OH,        —CONR⁷R⁸, oxo, —C₁₋₄ alkylene-NR⁷R⁸, —C₁₋₄ alkylene-NHOH, —C₁₋₄        alkyene-NR⁹COR¹⁰, —C₁₋₄ alkylene-NR⁹SO₂RO, —C₁₋₄        alkylene-NR⁹COOR¹⁰, —C₁₋₄ alkylene-NR⁹CONR⁷R⁸, —C₁₋₈        alkylene-NR⁹SO₂NR⁷R⁸, —C₁₋₄ alkylene-OH and —C₁₋₄        alkylene-CONR⁷R⁸. More preferably, there is only one group R³.

In one embodiment, the invention provides a compound of formula I, Ia,Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1, morepreferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is selected from D1, D2, D3 and D4:

wherein the cyclobutyl ring comprised in D1, the cyclopentyl ringcomprised in D2, the cyclohexyl ring comprised in D3 and the cycloheptylring comprised in D4 is optionally substituted with one further R³ andis optionally substituted with one or more R⁴, and wherein thecyclobutyl ring comprised in D1, the cyclopentyl ring comprised in D2,the cyclohexyl ring comprised in D3 and the cycloheptyl ring comprisedin D4 optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵ (option (a) applies only to D2,        D3 and D4 but not to D1); or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group (i.e., the cyclobutyl ring comprised in D1, the        cyclopentyl ring comprised in D2, the cyclohexyl ring comprised        in D3 or the cycloheptyl ring comprised in D4), wherein p is 1        or 2 and each R^(a) independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group (i.e., the        cyclobutyl ring comprised in D1, the cyclopentyl ring comprised        in D2, the cyclohexyl ring comprised in D3 or the cycloheptyl        ring comprised in D4) via a single carbon atom common to both        rings, and wherein said second ring is optionally substituted        with one or more R⁶; and        each R³ is independently selected from —NR⁷R⁸ and —C₁₋₄        alkylene-NR⁷R⁸. More preferably, there is only one group R³. In        a preferred embodiment, R⁷ and R⁸ are each hydrogen.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring comprised in D is optionally substitutedwith one further R³ and is optionally substituted with one or more R⁴,and wherein the cyclohexyl ring comprised in D optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group (i.e., the cyclohexyl ring), wherein p is 1 or        2 and each R^(a) independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group (i.e., the        cyclohexyl ring) via a single carbon atom common to both rings,        and wherein said second ring is optionally substituted with one        or more R⁶; and        each R³ is independently selected from —NR⁷R⁸, —NHOH, —NR⁹COR¹⁰,        —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —OH,        —CONR⁷R⁸, oxo, —C₁₋₄ alkylene-NR⁷R⁸, —C₁₋₄ alkylene-NHOH, —C₁₋₄        alkyene-NR⁹COR¹⁰, —C₁₋₄ alkylene-NR⁹SO₂R¹⁰, —C₁₋₄        alkylene-NR⁹COOR¹⁰, —C₁₋₄ alkylene-NR⁹CONR⁷R⁸, —C₁₋₄        alkylene-NR⁹SO₂NR⁷R⁸, —C₁₋₄ alkylene-OH and —C₁₋₄        alkylene-CONR⁷R⁸. More preferably, there is only one group R³.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring comprised in D is optionally substitutedwith one further R³ and is optionally substituted with one or more R⁴,and wherein the cyclohexyl ring comprised in D optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group (i.e., the cyclohexyl ring), wherein p is 1 or        2 and each R^(a) independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group (i.e., the        cyclohexyl ring) via a single carbon atom common to both rings,        and wherein said second ring is optionally substituted with one        or more R⁶; and        each R³ is independently selected from —NR⁷R⁸, —NHOH, —NR⁹COR¹⁰,        —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —OH, and oxo.        More preferably, there is only one group R³.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring comprised in D is optionally substitutedwith one further R³ and is optionally substituted with one or more R⁴,and wherein the cyclohexyl ring comprised in D optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group (i.e., the cyclohexyl ring), wherein p is 1 or        2 and each R^(a) independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group (i.e., the        cyclohexyl ring) via a single carbon atom common to both rings,        and wherein said second ring is optionally substituted with one        or more R⁶; and        each R³ is independently selected from —NR⁷R⁸ and        —C₁₋₄alkylene-NR⁷R⁸. More preferably, there is only one group        R³. In a preferred embodiment, R⁷ and R⁸ are each hydrogen.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group (i.e., the cyclohexyl ring), wherein p is 1 or        2 and each R^(a) independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group (i.e., the        cyclohexyl ring) via a single carbon atom common to both rings,        and wherein said second ring is optionally substituted with one        or more R⁶; and        R³ is selected from —NR⁷R⁸, —NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰,        —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —OH, —CONR⁷R⁸, oxo, —C₁₋₄        alkylene-NR⁷R⁸, —C₁₋₄ alkylene-NHOH, —C₁₋₄ alkyene-NR⁹COR¹⁰,        —C₁₋₄ alkylene-NR⁹SO₂R¹⁰, —C₁₋₄ alkylene-NR⁹COOR¹⁰, —C₁₋₄        alkylene-NR⁹CONR⁷R⁸, —C₁₋₄ alkylene-NR⁹SO₂NR⁷R⁸, —C₁₋₄        alkylene-OH and —C₁₋₄ alkylene-CONR⁷R⁸.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group (i.e., the cyclohexyl ring), wherein p is 1 or        2 and each R^(a) independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group (i.e., the        cyclohexyl ring) via a single carbon atom common to both rings,        and wherein said second ring is optionally substituted with one        or more R⁶; and        R³ is selected from —NR⁷R⁸, —NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰,        —NR⁹COOR¹⁰, —NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —OH, and oxo.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group (i.e., the cyclohexyl ring), wherein p is 1 or        2 and each R^(a) independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group (i.e., the        cyclohexyl ring) via a single carbon atom common to both rings,        and wherein said second ring is optionally substituted with one        or more R⁶; and        R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸. In a        preferred embodiment, R⁷ and R⁸ are each hydrogen.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group (i.e., the cyclohexyl ring), wherein p is 1 or        2 and each R^(a) independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group (i.e., the        cyclohexyl ring) via a single carbon atom common to both rings,        and wherein said second ring is optionally substituted with one        or more R⁶; and        R³ is —NR⁷R⁸.

In the above embodiment, R³ is preferably —NH₂. In another preferredembodiment, R³ is

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴; andR³ is selected from —NR⁷R⁸, —NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰,—NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —OH, —CONR⁷R⁸, oxo, —C₁₋₄ alkylene-NR⁷R⁸,—C₁₋₄ alkylene-NHOH, —C₁₋₄ alkyene-NR⁹COR¹⁰, —C₁₋₄ alkylene-NR⁹SO₂R¹⁰,—C₁₋₄ alkylene-NR⁹COOR¹⁰, —C₁₋₄ alkylene-NR⁹CONR⁷R⁸, —C₁₋₄alkylene-NR⁹SO₂NR⁷R⁸, —C₁₋₄ alkylene-OH and —C₁₋₄ alkylene-CONR⁷R⁸.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴; andR³ is selected from —NR⁷R⁸, —NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰,—NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —OH, and oxo.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴; andR³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸. In a preferredembodiment, R⁷ and R⁸ are each hydrogen.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴; andR³ is —NR⁷R⁸.

In the above embodiment, R³ is preferably —NH₂. In another preferredembodiment, R³ is

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

andR³ is selected from —NR⁷R⁸, —NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰,—NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —OH, —CONR⁷R⁸, oxo, —C₁₋₄ alkylene-NR⁷R⁸,—C₁₋₄ alkylene-NHOH, —C₁₋₄ alkyene-NR⁹COR¹⁰, —C₁₋₄ alkylene-NR⁹SO₂R¹⁰,—C₁₋₄ alkylene-NR⁹COOR¹, —C₁₋₄ alkylene-NR⁹CONR⁷R⁸, —C₁₋₄alkylene-NR⁹SO₂NR⁷R⁸, —C₁₋₄ alkylene-OH and —C₁₋₄ alkylene-CONR⁷R⁸.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

andR³ is selected from —NR⁷R⁸, —NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰,—NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —OH, and oxo.

In a preferred embodiment, the invention provides a compound of formulaI, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

andR³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸. In a preferredembodiment, R⁷ and R⁸ are each hydrogen.

In another preferred embodiment, the invention provides a compound offormula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia,or Ia-1, more preferably a compound of formula Ia or Ia-1, and mostpreferably a compound of formula Ia-1) wherein:

D is

andR³ is —NR⁷R⁸.

In the above embodiment, R³ is preferably —NH₂. In another preferredembodiment, R³ is

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclobutyl ring is optionally substituted with one or moreR⁴; andR³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸. In a preferredembodiment, R⁷ and R⁸ are each hydrogen.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclobutyl ring is optionally substituted with one or moreR⁴; andR³ is —NR⁷R⁸. In this embodiment, R³ is preferably —NH₂. In anotherpreferred embodiment, R³ is

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴; andR³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸. In a preferredembodiment, R⁷ and R⁸ are each hydrogen.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴; andR³ is —NR⁷R⁸. In this embodiment, R³ is preferably —NH₂. In anotherpreferred embodiment, R³ is

In another embodiment, the invention provides a compound of Formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein A is phenyl, naphthyl or monocyclicheteroaryl, wherein said phenyl, naphthyl or monocyclic heteroaryl isoptionally substituted with one or more (e.g., one or two) R¹. In a morepreferred embodiment, A is phenyl, naphthyl, pyridyl, thiophenyl,pyrrolyl, furanyl, or thiazolyl, wherein A is optionally substitutedwith one or more R¹. More preferably, A is phenyl, naphthyl, pyridyl orthiazolyl, wherein A is optionally substituted with one or more R¹.Still more preferably, A is phenyl, 2-naphthyl, 3-pyridyl or5-thiazolyl, wherein A is optionally substituted with one or more R¹. Inone embodiment, A is phenyl optionally substituted with one or more R¹.In another embodiment, A is naphthyl, preferably 2-naphthyl, optionallysubstituted with one or more R¹. In another embodiment, A is pyridyl,preferably 3-pyridyl, optionally substituted with one or more R¹. Inanother embodiment, A is thiazolyl, preferably 5-thiazolyl, optionallysubstituted with one or more R¹.

In another embodiment, the invention provides a compound of Formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein A is phenyl or monocyclic heteroaryl,wherein said phenyl or said monocyclic heteroaryl is optionallysubstituted with one or more (e.g., one or two) R¹. In a more preferredembodiment, A is phenyl, pyridyl, thiophenyl, pyrrolyl, furanyl, orthiazolyl, wherein A is optionally substituted with one or more R¹. Morepreferably, A is phenyl, pyridyl or thiazolyl, wherein A is optionallysubstituted with one or more R¹. In one embodiment, A is phenyl. Inanother embodiment, A is 3-pyridyl. In another embodiment, A is5-thiazolyl.

In another embodiment, the invention provides a compound of Formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein A is phenyl optionally substitutedwith one or more R¹.

In another embodiment, the invention provides a compound of Formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein A is naphthyl (e.g. 2-naphthyl)optionally substituted with one or more R¹.

In another embodiment, the invention provides a compound of Formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein A is heteroaryl optionally substitutedwith one or more R¹. Preferably, A is monocyclic heteroaryl optionallysubstituted with one or more R¹.

In another embodiment, the invention provides a compound of Formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

A is phenyl or monocyclic heteroaryl (preferably phenyl, pyridyl orthiazolyl, more preferably phenyl, 3-pyridyl or 5-thiazolyl), wherein Ais optionally substituted with one or more R¹;

B is hydrogen, R¹ or -L-E;

E is phenyl optionally substituted with one or more R²; and

L is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—, wherein said —CH₂—NH— or—CH₂—O— groups are linked to ring A through the N or O atom,respectively, and are linked to ring E through the —CH₂— group. In amore specific embodiment, L is a bond or —CH₂—O—, wherein said —CH₂—O—group is linked to ring A through the O atom and to ring E through the—CH₂— group.

In another embodiment, the invention provides a compound of Formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

A is aryl or heteroaryl, wherein said aryl or said heteroaryl isoptionally substituted with one or more R¹; and B is hydrogen or R¹.

In the above embodiment, preferably each R¹ is independently selectedfrom C₁₋₈ alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and C₃₋₆ cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C₃₋₆ cycloalkyl.

In another embodiment, the invention provides a compound of Formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

A is phenyl, naphthyl or monocyclic heteroaryl, wherein said phenyl,said naphthyl or said monocyclic heteroaryl is optionally substitutedwith one or more R¹; and

B is hydrogen or R¹.

In the above embodiment, preferably each R¹ is independently selectedfrom C₁₋₈ alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and C₃₋₆ cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C₃₋₆ cycloalkyl.

In another embodiment, the invention provides a compound of Formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

A is phenyl or monocyclic heteroaryl, wherein said phenyl or saidmonocyclic heteroaryl is optionally substituted with one or more R¹; and

B is hydrogen or R¹.

In the above embodiment, preferably each R¹ is independently selectedfrom C₁₋₈ alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and Cm cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C₃₋₆ cycloalkyl.

In another embodiment, the invention provides a compound of Formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl or5-thiazolyl), wherein A is optionally substituted with one or more R¹;and

B is hydrogen or R¹.

In the above embodiment, preferably each R¹ is independently selectedfrom C₁₋₈ alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and C₃₋₆ cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C₃₋₆ cycloalkyl.

In another embodiment, the invention provides a compound of Formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

A is naphthyl optionally substituted with one or more R¹; and

B is hydrogen or R¹.

In the above embodiment, preferably each R¹ is independently selectedfrom C₁₋₈ alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and Cm cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C₃₋₆ cycloalkyl.

In another embodiment, the invention provides a compound of Formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

A is phenyl, naphthyl or monocyclic heteroaryl; and

B is hydrogen.

In another embodiment, the invention provides a compound of Formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl or5-thiazolyl); and

B is hydrogen.

In another embodiment, the invention provides a compound of Formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

A is phenyl; and

B is hydrogen.

In another embodiment, the invention provides a compound of Formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

A is naphthyl; and

B is hydrogen.

In another embodiment, the invention provides a compound of Formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

A is heteroaryl, preferably monocyclic heteroaryl; and

B is hydrogen.

In another embodiment, the invention provides a compound of Formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

A is phenyl or monocyclic heteroaryl (preferably phenyl, pyridyl orthiazolyl, and more preferably phenyl, 3-pyridyl or 5-thiazolyl),wherein said phenyl or said monocyclic heteroaryl is optionallysubstituted with one or more R¹; and

B is -L-E. In the above embodiment preferably L is a bond, —O—, —NH—,—CH₂—NH—, or —CH₂—O—, wherein said —CH₂—NH— or —CH₂—O— groups are linkedto ring A through the N or O atom, respectively, and are linked to ringE through the —CH₂— group. In a more specific embodiment, E is phenyloptionally substituted with one or more R² and L is a bond, —O—, —NH—,—CH₂—NH—, or —CH₂—O—, wherein said —CH₂—NH— or —CH₂—O— groups are linkedto ring A through the N or O atom, respectively, and are linked to ringE through the —CH₂— group. Preferably, L is a bond or —CH₂—O—, whereinsaid —CH₂—O— group is linked to ring A through the O atom and to ring Ethrough the —CH₂— group.

In another embodiment, the invention provides a compound of Formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

A is phenyl or pyridyl (preferably phenyl or 3-pyridyl), wherein A isoptionally substituted with one or more R¹; and

B is -L-E. In the above embodiment preferably L is a bond, —O—, —NH—,—CH₂—NH—, or —CH₂—O—, wherein said —CH₂—NH— or —CH₂—O— groups are linkedto ring A through the N or O atom, respectively, and are linked to ringE through the —CH₂— group. In a more specific embodiment, E is phenyloptionally substituted with one or more R² and L is a bond, —O—, —NH—,—CH₂—NH—, or —CH₂—O—, wherein said —CH₂—NH— or —CH₂—O— groups are linkedto ring A through the N or O atom, respectively, and are linked to ringE through the —CH₂— group. Preferably, L is a bond or —CH₂—O—, whereinsaid —CH₂—O— group is linked to ring A through the O atom and to ring Ethrough the —CH₂— group.

In another embodiment, the invention provides a compound of Formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

A is phenyl; and

B is -L-E. In the above embodiment preferably L is a bond, —O—, —NH—,—CH₂—NH—, or —CH₂—O—, wherein said —CH₂—NH— or —CH₂—O— groups are linkedto ring A through the N or O atom, respectively, and are linked to ringE through the —CH₂— group. In a more specific embodiment, E is phenyloptionally substituted with one or more R² and L is a bond, —O—, —NH—,—CH₂—NH—, or —CH₂—O—, wherein said —CH₂—NH— or —CH₂—O— groups are linkedto ring A through the N or O atom, respectively, and are linked to ringE through the —CH₂— group. Preferably, L is a bond or —CH₂—O—, whereinsaid —CH₂—O— group is linked to ring A through the O atom and to ring Ethrough the —CH₂— group.

In another embodiment, the invention provides a compound of Formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

A is 3-pyridyl; and

B is -L-E. In the above embodiment preferably L is a bond, —O—, —NH—,—CH₂—NH—, or —CH₂—O—, wherein said —CH₂—NH— or —CH₂—O— groups are linkedto ring A through the N or O atom, respectively, and are linked to ringE through the —CH₂— group. In a more specific embodiment, E is phenyloptionally substituted with one or more R² and L is a bond, —O—, —NH—,—CH₂—NH—, or —CH₂—O—, wherein said —CH₂—NH— or —CH₂—O— groups are linkedto ring A through the N or O atom, respectively, and are linked to ringE through the —CH₂— group. Preferably, L is a bond or —CH₂—O—, whereinsaid —CH₂—O— group is linked to ring A through the O atom and to ring Ethrough the —CH₂— group.

In another embodiment, the invention provides a compound of Formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

B is -L-E;

L is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—, wherein the groups—CH₂—NH— and —CH₂—O— are linked to ring A through the N or O atom,respectively, and are linked to ring E through the —CH₂— group; and

E is aryl or heteroaryl, wherein said aryl or said heteroaryl isoptionally substituted with one or more R². In a specific embodiment,each R² is independently selected from hydroxyl, halo, haloC₁₋₈ alkyland N-sulfonamido.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group, wherein p is 1 or 2 and each R^(a)        independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group via a single carbon        atom common to both rings, and wherein said second ring is        optionally substituted with one or more R⁶;        A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl        or 5-thiazolyl), wherein A is optionally substituted with one or        more R¹;        B is hydrogen, R¹ or -L-E;        E is phenyl optionally substituted with one or more R²;        L is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—, wherein said        —CH₂—NH— or —CH₂—O— groups are linked to ring A through the N or        O atom, respectively, and are linked to ring E through the —CH₂—        group. Preferably, L is a bond or —CH₂—O—, wherein said —CH₂—O—        group is linked to ring A through the O atom and to ring E        through the —CH₂— group.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring s optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group, wherein p is 1 or 2 and each R^(a)        independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group via a single carbon        atom common to both rings, and wherein said second ring is        optionally substituted with one or more R⁶;        A is aryl or heteroaryl, wherein A is optionally substituted        with one or more R¹; and        B is hydrogen or R¹.

In the above embodiment, preferably each R¹ is independently selectedfrom C₁₋₈ alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and Cm cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C_(M) cycloalkyl.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group, wherein p is 1 or 2 and each R^(a)        independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group via a single carbon        atom common to both rings, and wherein said second ring is        optionally substituted with one or more R⁶;        A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl        or 5-thiazolyl), wherein A is optionally substituted with one or        more R¹; and        B is hydrogen or R¹.

In the above embodiment, preferably each R¹ is independently selectedfrom C₁₋₈ alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and Cm cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C₃₋₆ cycloalkyl.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group, wherein p is 1 or 2 and each R^(a)        independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group via a single carbon        atom common to both rings, and wherein said second ring is        optionally substituted with one or more R⁶;        A is phenyl optionally substituted with one or more R¹; and        B is hydrogen or R¹.

In the above embodiment, preferably each R¹ is independently selectedfrom C₁₋₈ alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and C₃₋₆ cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C₃₋₆-cycloalkyl.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group, wherein p is 1 or 2 and each R^(a)        independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group via a single carbon        atom common to both rings, and wherein said second ring is        optionally substituted with one or more R⁶;        A is aryl or heteroaryl (preferably phenyl, naphthyl, pyridyl or        thiazolyl); and        B is hydrogen.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group, wherein p is 1 or 2 and each R^(a)        independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group via a single carbon        atom common to both rings, and wherein said second ring is        optionally substituted with one or more R⁶;        A is phenyl; and        B is hydrogen.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group, wherein p is 1 or 2 and each R^(a)        independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group via a single carbon        atom common to both rings, and wherein said second ring is        optionally substituted with one or more R⁶;        A is phenyl or pyridyl (preferably phenyl or 3-pyridyl), wherein        A is optionally substituted with one or more R¹; and        B is -L-E. Preferably L is a bond, —O—, —NH—, —CH₂—NH—, or        —CH₂—O—, wherein said —CH₂—NH— or —CH₂—O— groups are linked to        ring A through the N or O atom, respectively, and are linked to        ring E through the —CH₂— group. In a more specific embodiment, E        is phenyl optionally substituted with one or more R² and L is a        bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—, wherein said —CH₂—NH— or        —CH₂—O— groups are linked to ring A through the N or O atom,        respectively, and are linked to ring E through the —CH₂— group.        Preferably, L is a bond or —CH₂₋O—, wherein said —CH₂—O— group        is linked to ring A through the O atom and to ring E through the        —CH₂— group.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group, wherein p is 1 or 2 and each R^(a)        independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group via a single carbon        atom common to both rings, and wherein said second ring is        optionally substituted with one or more R⁶;        R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸;        A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl        or 5-thiazolyl), wherein A is optionally substituted with one or        more R¹;        B is hydrogen, R¹ or -L-E;        E is phenyl optionally substituted with one or more R²;        L is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—, wherein said        —CH₂—NH— or —CH₂—O— groups are linked to ring A through the N or        O atom, respectively, and are linked to ring E through the —CH₂—        group. Preferably, L is a bond or —CH₂—O—, wherein said —CH₂—O—        group is linked to ring A through the O atom and to ring E        through the —CH₂— group.

In a preferred embodiment of the above embodiment, R³ is —NR⁷R⁸. Morepreferably R³ is —NH₂. In another preferred embodiment, R³ is

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group, wherein p is 1 or 2 and each R^(a)        independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group via a single carbon        atom common to both rings, and wherein said second ring is        optionally substituted with one or more R⁶;        R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸;        A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl        or 5-thiazolyl), wherein A is optionally substituted with one or        more R¹;        B is hydrogen, R¹ or -L-E;        E is phenyl optionally substituted with one or more R²;        L is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—, wherein said        —CH₂—NH— or —CH₂—O— groups are linked to ring A through the N or        O atom, respectively, and are linked to ring E through the —CH₂—        group. Preferably, L is a bond or —CH₂—O—, wherein said —CH₂—O—        group is linked to ring A through the O atom and to ring E        through the —CH₂— group.

In a preferred embodiment of the above embodiment, R³ is —NR⁷R⁸. Morepreferably R³ is —NH₂.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group, wherein p is 1 or 2 and each R^(a)        independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group via a single carbon        atom common to both rings, and wherein said second ring is        optionally substituted with one or more R⁶;        R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸;        A is aryl or heteroaryl, wherein A is optionally substituted        with one or more R¹; and        B is hydrogen or R¹.

In a preferred embodiment of the above embodiment, R³ is —NR⁷R⁸. Morepreferably R³ is —NH₂.

Preferably in the above embodiment each R¹ is independently selectedfrom C₁₋₈ alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and C₃₋₆ cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C₃₋₆ cycloalkyl.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group, wherein p is 1 or 2 and each R^(a)        independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group via a single carbon        atom common to both rings, and wherein said second ring is        optionally substituted with one or more R⁶;        R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸;        A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl        or 5-thiazolyl), wherein A is optionally substituted with one or        more R¹; and        B is hydrogen or R¹.

In a preferred embodiment of the above embodiment, R³ is —NR⁷R⁸. Morepreferably R³ is —NH₂. In another preferred embodiment, R³ is

Preferably in the above embodiment each R¹ is independently selectedfrom C₁₋₈ alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and C₃₋₆ cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C₃₋₆ cycloalkyl.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group, wherein p is 1 or 2 and each R^(a)        independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group via a single carbon        atom common to both rings, and wherein said second ring is        optionally substituted with one or more R⁶;        R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸;        A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl        or 5-thiazolyl), wherein A is optionally substituted with one or        more R¹; and        B is hydrogen or R¹.

In a preferred embodiment of the above embodiment, R³ is —NR⁷R⁸. Morepreferably R³ is —NH₂.

Preferably in the above embodiment each R¹ is independently selectedfrom C₁₋₈ alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and C₃₋₈ cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C₃₋₆ cycloalkyl.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group, wherein p is 1 or 2 and each R^(a)        independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group via a single carbon        atom common to both rings, and wherein said second ring is        optionally substituted with one or more R⁶;        R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸;        A is phenyl optionally substituted with one or more R¹; and        B is hydrogen or R¹.

In a preferred embodiment of the above embodiment, R³ is —NR⁷R⁸. Morepreferably R³ is —NH₂.

Preferably in the above embodiment each R¹ is independently selectedfrom C₁₋₈ alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, sulfonamide, C₁₋₄ alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and C₆ cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C₃₋₆cycloalkyl.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group, wherein p is 1 or 2 and each R^(a)        independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group via a single carbon        atom common to both rings, and wherein said second ring is        optionally substituted with one or more R⁶;        R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸;        A is phenyl; and        B is hydrogen.

In a preferred embodiment of the above embodiment, R³ is —NR⁷R⁸. Morepreferably R³ is —NH₂. In another preferred embodiment, R³ is

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group, wherein p is 1 or 2 and each R^(a)        independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group via a single carbon        atom common to both rings, and wherein said second ring is        optionally substituted with one or more R⁶;        R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸;        A is phenyl; and        B is hydrogen.

In a preferred embodiment of the above embodiment, R³ is —NR⁷R⁸. Morepreferably R³ is —NH₂.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group, wherein p is 1 or 2 and each R^(a)        independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group via a single carbon        atom common to both rings, and wherein said second ring is        optionally substituted with one or more R⁶;        R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸;        A is phenyl or pyridyl (preferably phenyl or 3-pyridyl), wherein        A is optionally substituted with one or more R¹; and B is -L-E.        Preferably L is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—, wherein        said —CH₂—NH— or —CH₂—O— groups are linked to ring A through the        N or O atom, respectively, and are linked to ring E through the        —CH₂— group. In a more specific embodiment, E is phenyl        optionally substituted with one or more R² and L is a bond, —O—,        —NH—, —CH₂—NH—, or —CH₂—O—, wherein said —CH₂—NH— or —CH₂—O—        groups are linked to ring A through the N or O atom,        respectively, and are linked to ring E through the —CH₂— group.        Preferably, L is a bond or —CH₂—O—, wherein said —CH₂—O— group        is linked to ring A through the O atom and to ring E through the        —CH₂— group.

In a preferred embodiment of the above embodiment, R³ is —NR⁷R⁸. Morepreferably R³ is —NH₂. In another preferred embodiment, R³ is

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴, and wherein the cyclohexyl ring optionally:

-   -   (a) is fused to a phenyl or a 5- or 6-membered aromatic        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said fused        phenyl or said fused aromatic heterocyclic ring is optionally        substituted with one or more R⁵; or    -   (b) is bonded to a linker group —(C(R^(a))₂)_(p)— linking        together any two non-adjacent ring carbon atoms of the        cycloalkyl group, wherein p is 1 or 2 and each R^(a)        independently is hydrogen or C₁₋₄ alkyl; or    -   (c) is linked to a second ring that is either a 3- to 7-membered        saturated carbocyclic ring or a 3- to 7-membered saturated        heterocyclic ring containing from 1 to 3 heteroatoms        independently selected from N, O and S, wherein said second ring        is linked together with the cycloalkyl group via a single carbon        atom common to both rings, and wherein said second ring is        optionally substituted with one or more R⁶;        R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸;        A is phenyl or pyridyl (preferably phenyl or 3-pyridyl), wherein        A is optionally substituted with one or more R¹; and        B is -L-E. Preferably L is a bond, —O—, —NH—, —CH₂—NH—, or        —CH₂—O—, wherein said —CH₂—NH— or —CH₂—O— groups are linked to        ring A through the N or O atom, respectively, and are linked to        ring E through the —CH₂— group. In a more specific embodiment, E        is phenyl optionally substituted with one or more R² and L is a        bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—, wherein said —CH₂—NH— or        —CH₂—O— groups are linked to ring A through the N or O atom,        respectively, and are linked to ring E through the —CH₂— group.        Preferably, L is a bond or —CH₂—O—, wherein said —CH₂—O— group        is linked to ring A through the O atom and to ring E through the        —CH₂— group.

In a preferred embodiment of the above embodiment, R³ is —NR⁷R⁸. Morepreferably R³ is —NH₂.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is selected from —NR⁷R⁸, —NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰,—NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —OH, —CONR⁷R⁸, oxo, —C₁₋₄ alkylene-NR⁷R⁸,—C₁₋₄ alkylene-NHOH, —C₁₋₄ alkyene-NR⁹COR¹⁰, —C₁₋₄ alkylene-NR⁹SO₂R¹⁰,—C₁₋₄ alkylene-NR⁹COOR¹⁰, —C₁₋₄ alkylene-NR⁹NR⁷R⁸, —C₁₋₄alkylene-NR⁹SO₂NR⁷R⁸, —C₁₋₄ alkylene-OH and —C₁₋₄ alkylene-CONR⁷R⁸;A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl or5-thiazolyl), wherein A is optionally substituted with one or more R¹;B is hydrogen, R¹ or -L-E;E is phenyl optionally substituted with one or more R²;L is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—, wherein said —CH₂—NH— or—CH₂—O— groups are linked to ring A through the N or O atom,respectively, and are linked to ring E through the —CH₂— group.Preferably, L is a bond or —CH₂—O—, wherein said —CH₂—O— group is linkedto ring A through the O atom and to ring E through the —CH₂— group.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is selected from —NR⁷R⁸, —NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰,—NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —OH, —CONR⁷R⁸, oxo, —C₁₋₄ alkylene-NR⁷R⁸,—C₁₋₄ alkylene-NHOH, —C₁₋₄ alkyene-NR⁹COR¹⁰, —C₁₋₄ alkylene-NR⁹SO₂R¹⁰,—C₁₋₄ alkylene-NR⁹COOR¹⁰, —C₁₋₄ alkylene-NR⁹CONR⁷R⁸, —C₁₋₄alkylene-NR⁹SO₂NR⁷R⁸, —C₁₋₄ alkylene-OH and —C₁₋₄ alkylene-CONR⁷R⁸;A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl or5-thiazolyl), wherein A is optionally substituted with one or more R¹;andB is hydrogen or R¹.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is selected from —NR⁷R⁸, —NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰,—NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —OH, —CONR⁷R⁸, oxo, —C₁₋₄ alkylene-NR⁷R⁸,—C₁₋₄ alkylene-NHOH, —C₁₋₄ alkyene-NR⁹COR¹⁰, —C₁₋₄ alkylene-NR⁹SO₂R¹⁰,—C₁₋₄ alkylene-NR⁹COOR¹⁰, —C₁₋₄ alkylene-NR⁹CONR⁷R⁸, —C₁₋₄alkylene-NR⁹SO₂NR⁷R⁸, —C₁₋₄ alkylene-OH and —C₁₋₄ alkylene-CONR⁷R⁸;A is phenyl; andB is hydrogen.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is selected from —NR⁷R⁸, —NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R¹, —NR⁹COOR¹⁰,—NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —OH, —CONR⁷R⁸, oxo, —C₁₋₄ alkylene-NR⁷R⁸,—C₁₋₄ alkylene-NHOH, —C₁₋₄ alkyene-NR⁹COR¹⁰, —C₁₋₄ alkylene-NR⁹SO₂R¹,—C₁₋₄ alkylene-NR⁹COOR^(1′), —C₁₋₄ alkylene-NR⁹CONR⁷R⁸, —C₁₋₄alkylene-NR⁹SO₂NR⁷R⁸, —C₁₋₄ alkylene-OH and —C₁₋₄ alkylene-CONR⁷R⁸;A is phenyl or pyridyl (preferably phenyl or 3-pyridyl), wherein A isoptionally substituted with one or more R¹; andB is -L-E. Preferably L is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—,wherein said —CH₂—NH— or —CH₂—O— groups are linked to ring A through theN or O atom, respectively, and are linked to ring E through the —CH₂—group. In a more specific embodiment, E is phenyl optionally substitutedwith one or more R² and L is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—,wherein said —CH₂—NH— or —CH₂—O— groups are linked to ring A through theN or O atom, respectively, and are linked to ring E through the —CH₂—group. Preferably, L is a bond or —CH₂—O—, wherein said —CH₂—O— group islinked to ring A through the O atom and to ring E through the —CH₂—group.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is selected from —NR⁷R⁸, —NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰,—NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —OH, and oxo;A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl or5-thiazolyl), wherein A is optionally substituted with one or more R¹;B is hydrogen, R¹ or -L-E;E is phenyl optionally substituted with one or more R²;L is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—, wherein said —CH₂—NH— or—CH₂—O— groups are linked to ring A through the N or O atom,respectively, and are linked to ring E through the —CH₂— group.Preferably, L is a bond or —CH₂—O—, wherein said —CH₂—O— group is linkedto ring A through the O atom and to ring E through the —CH₂— group.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is selected from —NR⁷R⁸, —NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R⁰, —NR⁹COOR¹⁰,—NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —OH, and oxo;A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl or5-thiazolyl), wherein A is optionally substituted with one or more R¹;andB is hydrogen or R¹.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is selected from —NR⁷R⁸, —NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰,—NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —OH, and oxo;A is phenyl; andB is hydrogen.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is selected from —NR⁷R⁸, —NHOH, —NR⁹COR¹⁰, —NR⁹SO₂R¹⁰, —NR⁹COOR¹⁰,—NR⁹CONR⁷R⁸, —NR⁹SO₂NR⁷R⁸, —OH, and oxo;A is phenyl or pyridyl (preferably phenyl or 3-pyridyl), wherein A isoptionally substituted with one or more R¹; andB is -L-E. Preferably L is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—,wherein said —CH₂—NH— or —CH₂—O— groups are linked to ring A through theN or O atom, respectively, and are linked to ring E through the —CH₂—group. In a more specific embodiment, E is phenyl optionally substitutedwith one or more R² and L is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—,wherein said —CH₂—NH— or —CH₂—O— groups are linked to ring A through theN or O atom, respectively, and are linked to ring E through the —CH₂—group. Preferably, L is a bond or —CH₂—O—, wherein said —CH₂—O— group islinked to ring A through the O atom and to ring E through the —CH₂—group.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸;A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl or5-thiazolyl), wherein A is optionally substituted with one or more R¹;B is hydrogen, R¹ or -L-E;E is phenyl optionally substituted with one or more R²;L is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—, wherein said —CH₂—NH— or—CH₂—O— groups are linked to ring A through the N or O atom,respectively, and are linked to ring E through the —CH₂— group.Preferably, L is a bond or —CH₂—O—, wherein said —CH₂—O— group is linkedto ring A through the O atom and to ring E through the —CH₂— group.

In a more specific embodiment of the above embodiment, R³ is —NH₂. Inanother specific embodiment, R³ is

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸;A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl or5-thiazolyl), wherein A is optionally substituted with one or more R¹;B is hydrogen, R¹ or -L-E;E is phenyl optionally substituted with one or more R²;L is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—, wherein said —CH₂—NH— or—CH₂—O— groups are linked to ring A through the N or O atom,respectively, and are linked to ring E through the —CH₂— group.Preferably, L is a bond or —CH₂—O—, wherein said —CH₂—O— group is linkedto ring A through the O atom and to ring E through the —CH₂— group.

In a more specific embodiment of the above embodiment, R³ is —NH₂.

In a preferred embodiment, the invention provides a compound of formulaI, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

R³ wherein the cyclohexyl ring is optionally substituted with one ormore R⁴;

R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸;

A is aryl or heteroaryl, wherein said aryl or said heteroaryl isoptionally substituted with one or more R¹; and

B is hydrogen or R¹.

Preferably in the above embodiment each R¹ is independently selectedfrom C₁₋₈ alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and C₃₋₈ cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C_(M) cycloalkyl.

In a more specific embodiment of the above embodiment, R³ is —NH₂.

In a more preferred embodiment, the invention provides a compound offormula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia,or Ia-1, more preferably a compound of formula Ia or Ia-1, and mostpreferably a compound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸;A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl or5-thiazolyl), wherein A is optionally substituted with one or more R¹;andB is hydrogen or R¹.

Preferably in the above embodiment each R¹ is independently selectedfrom C₁₋₈ alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and C₃₋₅ cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C_(M) cycloalkyl.

In a more specific embodiment of the above embodiment, R³ is —NH₂. Inanother specific embodiment, R³ is

In a more preferred embodiment, the invention provides a compound offormula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia,or Ia-1, more preferably a compound of formula Ia or Ia-1, and mostpreferably a compound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸;A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl or5-thiazolyl), wherein A is optionally substituted with one or more R¹;andB is hydrogen or R¹.

Preferably in the above embodiment each R¹ is independently selectedfrom C₁₋₈ alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁alkoxy, cyano, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and C₃₋₆ cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C₃₋₆ cycloalkyl.

In a more specific embodiment of the above embodiment, R³ is —NH₂.

In a still more preferred embodiment, the invention provides a compoundof formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I,Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and mostpreferably a compound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸;A is phenyl optionally substituted with one or more R¹; andB is hydrogen or R¹.

Preferably in the above embodiment each R¹ is independently selectedfrom C₁₋₈ alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and C₃₋₆ cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C₃₋₆ cycloalkyl.

In a more specific embodiment of the above embodiment, R³ is —NH₂.

In another preferred embodiment, the invention provides a compound offormula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia,or Ia-1, more preferably a compound of formula Ia or Ia-1, and mostpreferably a compound of formula Ia-1) wherein:

D is wherein the cyclohexyl ring is optionally substituted with one ormore R⁴;

R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸;

A is napthyl optionally substituted with one or more R¹; and

B is hydrogen or R¹.

Preferably in the above embodiment each R¹ is independently selectedfrom C₁₋₈ alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and C₃₋₆ cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C₃₋₆ cycloalkyl.

In a more specific embodiment of the above embodiment, R³ is —NH₂.

In another preferred embodiment, the invention provides a compound offormula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia,or Ia-1, more preferably a compound of formula Ia or Ia-1, and mostpreferably a compound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸;A is heteroaryl, preferably monocyclic heteroaryl, optionallysubstituted with one or more R¹; andB is hydrogen or R¹.

Preferably in the above embodiment each R¹ is independently selectedfrom C₁₋₈ alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, sulfonamide, C_s alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and C₃₋₆ cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C₃₋₆ cycloalkyl.

In a more specific embodiment of the above embodiment, R³ is —NH₂.

In another preferred embodiment, the invention provides a compound offormula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia,or Ia-1, more preferably a compound of formula Ia or Ia-1, and mostpreferably a compound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸;A is phenyl; andB is hydrogen.

In a more specific embodiment of the above embodiment, R³ is —NH₂. Inanother specific embodiment, R³ is

In another preferred embodiment, the invention provides a compound offormula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia,or Ia-1, more preferably a compound of formula Ia or Ia-1, and mostpreferably a compound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸;A is phenyl; andB is hydrogen.

In a more specific embodiment of the above embodiment, R³ is —NH₂.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is selected from —NR⁷R⁸ and —C₁₋₄alkylene-NR⁷R⁸;A is phenyl or pyridyl (preferably phenyl or 3-pyridyl), wherein A isoptionally substituted with one or more R¹; andB is -L-E. Preferably L is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—,wherein said —CH₂—NH— or —CH₂—O— groups are linked to ring A through theN or O atom, respectively, and are linked to ring E through the —CH₂—group. In a more specific embodiment, E is phenyl optionally substitutedwith one or more R² and L is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—,wherein said —CH₂—NH— or —CH₂—O— groups are linked to ring A through theN or O atom, respectively, and are linked to ring E through the —CH₂—group. Preferably, L is a bond or —CH₂—O—, wherein said —CH₂—O— group islinked to ring A through the O atom and to ring E through the —CH₂—group.

In a more specific embodiment of the above embodiment, R³ is —NH₂.

In a preferred embodiment, the invention provides a compound of formulaI, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is —NR⁷R⁸;A is aryl or heteroaryl (e.g., phenyl, naphthyl or monocyclicheteroaryl), wherein said aryl or said heteroaryl is optionallysubstituted with one or more R¹; andB is hydrogen, R¹ or -L-E.

In a more specific embodiment of the above embodiment, R³ is —NH₂.

In another preferred embodiment, the invention provides a compound offormula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia,or Ia-1, more preferably a compound of formula Ia or Ia-1, and mostpreferably a compound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is —NR⁷R⁸;A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl or5-thiazolyl), wherein A is optionally substituted with one or more R¹;andB is hydrogen, R¹ or -L-E.

In a more specific embodiment of the above embodiment, R³ is —NH₂.

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is —NR⁷R⁸;A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl or5-thiazolyl), wherein A is optionally substituted with one or more R¹;B is hydrogen, R¹ or -L-E;E is phenyl optionally substituted with one or more R²;L is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—, wherein said —CH₂—NH— or—CH₂—O— groups are linked to ring A through the N or O atom,respectively, and are linked to ring E through the —CH₂— group.Preferably, L is a bond or —CH₂—O—, wherein said —CH₂—O— group is linkedto ring A through the O atom and to ring E through the —CH₂— group.

In a more specific embodiment of the above embodiment, R³ is —NH₂. Inanother specific embodiment, R³ is

In another embodiment, the invention provides a compound of formula I,Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is —NR⁷R⁸;A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl or5-thiazolyl), wherein A is optionally substituted with one or more R¹;B is hydrogen, R¹ or -L-E;E is phenyl optionally substituted with one or more R²;L is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—, wherein said —CH₂—NH— or—CH₂—O— groups are linked to ring A through the N or O atom,respectively, and are linked to ring E through the —CH₂— group.Preferably, L is a bond or —CH₂—O—, wherein said —CH₂—O— group is linkedto ring A through the O atom and to ring E through the —CH₂— group.

In a more specific embodiment of the above embodiment, R³ is —NH₂.

In a preferred embodiment, the invention provides a compound of formulaI, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia, or Ia-1,more preferably a compound of formula Ia or Ia-1, and most preferably acompound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is —NR⁷R⁸;A is aryl or heteroaryl (e.g., phenyl, naphthyl or monocyclicheteroaryl), wherein said aryl or said heteroaryl is optionallysubstituted with one or more R¹; andB is hydrogen or R¹.

In a more specific embodiment of the above embodiment, R³ is —NH₂.

Preferably in the above embodiments each R¹ is independently selectedfrom C₁a alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and C₃₋₆ cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C₃₋₆cycloalkyl.

In a more preferred embodiment, the invention provides a compound offormula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia,or Ia-1, more preferably a compound of formula Ia or Ia-1, and mostpreferably a compound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is —NR⁷R⁸;A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl or5-thiazolyl), wherein A is optionally substituted with one or more R¹;andB is hydrogen or R¹.In a more specific embodiment of the above embodiment, R³ is —NH₂. Inanother specific embodiment, R³ is

Preferably in the above embodiments each R¹ is independently selectedfrom C₁₋₈ alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and C₃₋₆ cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C₃₋₆ cycloalkyl.

In a more preferred embodiment, the invention provides a compound offormula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia,or Ia-1, more preferably a compound of formula Ia or Ia-1, and mostpreferably a compound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is —NR⁷R⁸;A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl or5-thiazolyl), wherein A is optionally substituted with one or more R¹;andB is hydrogen or R¹.

In a more specific embodiment of the above embodiment, R³ is —NH₂.

Preferably in the above embodiments each R¹ is independently selectedfrom C₁₋₈ alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and C₃₋₆ cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C₃₋₆cycloalkyl.

In another preferred embodiment, the invention provides a compound offormula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia,or Ia-1, more preferably a compound of formula Ia or Ia-1, and mostpreferably a compound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is —NR⁷R⁸;A is phenyl optionally substituted with one or more R¹; andB is hydrogen or R¹.

In a more specific embodiment of the above embodiment, R³ is —NH₂.

Preferably in the above embodiments each R¹ is independently selectedfrom C₁₋₈ alkyl, amino, amido, hydroxyl, halo, haloC₁₋₈ alkyl, haloC₁₋₈alkoxy, cyano, sulfonamide, C₁₋₈ alkoxy, acyl, carboxyl, carbamate, andurea. In another preferred embodiment, each R¹ is independently selectedfrom halo, C₁₋₄ alkyl (e.g. methyl), haloC₁₋₄ alkyl (e.g.trifluoromethyl), C₁₋₄ alkoxy (e.g. methoxy) and C₃₋₆ cycloalkyl (e.g.cyclopropyl). In another preferred embodiment, each R¹ is independentlyselected from halo, C₁₋₄ alkyl and C₃₋₆cycloalkyl.

In a very preferred embodiment, the invention provides a compound offormula I, Ia, Ia-1, Ib or Ic wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is —NR⁷R⁸;A is phenyl, naphthyl or monocyclic heteroaryl; andB is hydrogen.

In a more specific embodiment of the above embodiment, R³ is —NH₂. Inanother very preferred embodiment, the invention provides a compound offormula I, Ia, Ia-1, Ib or Ic wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is —NR⁷R⁸;A is phenyl, pyridyl or thiazolyl (preferably phenyl, 3-pyridyl or5-thiazolyl); andB is hydrogen.

In a more specific embodiment of the above embodiment, R³ is —NH₂. Inanother very preferred embodiment, the invention provides a compound offormula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia,or Ia-1, more preferably a compound of formula Ia or Ia-1, and mostpreferably a compound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is —NR⁷R⁸;A is phenyl; andB is hydrogen.

In a more specific embodiment of the above embodiment, R³ is —NH₂. Inanother specific embodiment, R³ is

In another very preferred embodiment, the invention provides a compoundof formula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I,Ia, or Ia-1, more preferably a compound of formula Ia or Ia-1, and mostpreferably a compound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is —NR⁷R⁸;A is phenyl; andB is hydrogen.

In a more specific embodiment of the above embodiment, R³ is —NH₂.

In another preferred embodiment, the invention provides a compound offormula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia,or Ia-1, more preferably a compound of formula Ia or Ia-1, and mostpreferably a compound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is —NR⁷R⁸;A is phenyl or pyridyl (preferably phenyl or 3-pyridyl), wherein A isoptionally substituted with one or more R¹; andB is -L-E.

Preferably, L is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—, wherein said—CH₂—NH— or —CH₂—O— groups are linked to ring A through the N or O atom,respectively, and are linked to ring E through the —CH₂— group; morepreferably, L is a bond or —CH₂—O—, wherein said —CH₂—O— group is linkedto ring A through the O atom and to ring E through the —CH₂— group.

In a more specific embodiment of the above embodiment, R³ is —NH₂. Inanother specific embodiment, R³ is

In another preferred embodiment, the invention provides a compound offormula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia,or Ia-1, more preferably a compound of formula Ia or Ia-1, and mostpreferably a compound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is —NR⁷R⁸;A is phenyl or pyridyl (preferably phenyl or 3-pyridyl), wherein A isoptionally substituted with one or more R¹; andB is -L-E.

Preferably, L is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—, wherein said—CH₂—NH— or —CH₂—O— groups are linked to ring A through the N or O atom,respectively, and are linked to ring E through the —CH₂— group; morepreferably, L is a bond or —CH₂—O—, wherein said —CH₂—O— group is linkedto ring A through the O atom and to ring E through the —CH₂— group.

In a more specific embodiment of the above embodiment, R³ is —NH₂.

In another preferred embodiment, the invention provides a compound offormula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia,or Ia-1, more preferably a compound of formula Ia or Ia-1, and mostpreferably a compound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is —NR⁷R⁸;A is phenyl or pyridyl (preferably phenyl or 3-pyridyl), wherein A isoptionally substituted with one or more R¹;B is -L-E;E is phenyl optionally substituted with one or more R²; andL is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—, wherein said —CH₂—NH— or—CH₂—O— groups are linked to ring A through the N or O atom,respectively, and are linked to ring E through the —CH₂— group, andpreferably, L is a bond or —CH₂—O—, wherein said —CH₂—O— group is linkedto ring A through the O atom and to ring E through the —CH₂— group.

In a more specific embodiment of the above embodiment, R³ is —NH₂. Inanother specific embodiment, R³ is

In another preferred embodiment, the invention provides a compound offormula I, Ia, Ia-1, Ib or Ic (preferably a compound of formula I, Ia,or Ia-1, more preferably a compound of formula Ia or Ia-1, and mostpreferably a compound of formula Ia-1) wherein:

D is

wherein the cyclohexyl ring is optionally substituted with one or moreR⁴;R³ is —NR⁷R⁸;A is phenyl or pyridyl (preferably phenyl or 3-pyridyl), wherein A isoptionally substituted with one or more R¹;B is -L-E;E is phenyl optionally substituted with one or more R²; andL is a bond, —O—, —NH—, —CH₂—NH—, or —CH₂—O—, wherein said —CH₂—NH— or—CH₂—O— groups are linked to ring A through the N or O atom,respectively, and are linked to ring E through the —CH₂— group, andpreferably, L is a bond or —CH₂—O—, wherein said —CH₂—O— group is linkedto ring A through the O atom and to ring E through the —CH₂— group.

In a more specific embodiment of the above embodiment, R³ is —NH₂.

In a further embodiment, the invention provides a compound of formula I,Ia or Ia-1 selected from:

-   N1-((trans)-2-phenylcyclopropyl)cyclohexane-1,4-diamine;-   (cis)-N1-((1S,2R)-2-phenylcyclopropyl)cyclohexane-1,4-diamine;-   (trans)-N1-((1S,2R)-2-phenylcyclopropyl)cyclohexane-1,4-diamine;-   (cis)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine;-   (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-(thiazol-5-yl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine;-   4-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)cyclohexanol;-   4-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)cyclohexanecarboxamide;-   N-(4-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)cyclohexyl)acetamide;-   (R)-1-(4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl)pyrrolidin-3-amine;-   N1-((trans)-2-(4′-chloro-[1,1′-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-(3′-chloro-[1,1′-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine;-   4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-ol;-   N-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)methanesulfonamide;-   N1-((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-methyl-N4-((trans)-2-phenylcyclopropyl)cyclohexane-1,4-diamine;-   N1-methyl-N4-((trans)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)-N4-methylcyclohexane-1,4-diamine;-   N1-((trans)-2-phenylcyclopropyl)cyclobutane-1,3-diamine;-   N1-((trans)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)cyclobutane-1,3-diamine;-   N1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)cyclobutane-1,3-diamine;-   N1-((trans)-2-phenylcyclopropyl)-2,3-dihydro-1H-indene-1,3-diamine;-   N1-((trans)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)-2,3-dihydro-1H-indene-1,3-diamine;-   N1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)-2,3-dihydro-1H-indene-1,3-diamine;-   N1-((trans)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1,4-diamine;-   N1-((1S,2S)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1,4-diamine;-   N1-((1R,2R)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1,4-diamine;-   1-methyl-N4-((trans)-2-phenylcyclopropyl)cyclohexane-1,4-diamine;-   4-(aminomethyl)-N-((trans)-2-phenylcyclopropyl)cyclohexanamine;-   N1-((trans)-2-phenylcyclopropyl)cyclohexane-1,3-diamine;-   N1-((cis)-2-phenylcyclopropyl)cyclohexane-1,4-diamine;-   Tert-butyl    (4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl)carbamate;-   1-ethyl-3-(4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl)urea;-   4-morpholino-N-((trans)-2-phenylcyclopropyl)cyclohexanamine;-   N1-((trans)-2-(4-bromophenyl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-(2-(o-tolyl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-(2-(4-(trifluoromethyl)phenyl)cyclopropyl)cyclohexane-1,4-diamine-   N1-(2-(4-methoxyphenyl)cyclopropyl)cyclohexane-1,4-diamine;-   4-(2-((4-aminocyclohexyl)amino)cyclopropyl)phenol;-   N1-(2-(2-fluorophenyl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-(2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-(2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-(2-methyl-2-phenylcyclopropyl)cyclohexane-1,4-diamine;-   (R)-1-(4-(((trans)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)    amino)cyclohexyl)pyrrolidin-3-amine;-   (Cis)-N1-((1S,2R)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine;-   (Trans)-N1-((1S,2R)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclo-propyl)cyclohexane-1,4-diamine;-   (Cis)-N1-((1R,2S)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclo-propyl)cyclohexane-1,4-diamine;-   (Trans)-N1-((1R,2S)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclo-propyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-(4-cyclopropylphenyl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-(4-(pyridin-3-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-(4-(1H-indazol-6-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-(4-(1H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;-   3-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)thiophen-2-yl)phenol;-   3-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)thiazol-2-yl)phenol;-   3-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)pyridin-2-yl)-5-methoxybenzonitrile;-   5-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)pyridin-2-yl)-2-methylphenol;-   N-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-6-methoxy-[1,1′-biphenyl]-3-yl)methanesulfonamide;-   N-(3-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)thiazol-2-yl)phenyl)-2-cyanobenzenesulfonamide-   N-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)-2-cyanobenzenesulfonamide;-   6-amino-N-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)pyridine-3-sulfonamide;-   N-4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)piperazine-1-sulfonamide;-   N1-((cis)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-(4-((3-(piperazin-1-yl)benzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-(4-(pyridin-3-ylmethoxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-(6-((3-methyl    benzyl)amino)pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine;-   3-((5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)pyridin-2-yl)    amino)benzonitrile;-   N1-((trans)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-(o-tolyl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-(4-methoxyphenyl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-(2-fluorophenyl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1,4-diamine;-   N1-((trans)-2-methyl-2-phenylcyclopropyl)cyclohexane-1,4-diamine;-   (cis)-N1-((1S,2R)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine;-   (trans)-N1-((1R,2S)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine;-   (cis)-N1-((1R,2S)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine;-   (trans)-N1-((1S,2R)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine;-   (cis)-N1-((1S,2R)-2-phenylcyclopropyl)cyclobutane-1,3-diamine;-   (trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclobutane-1,3-diamine;-   (cis)-N1-((1R,2S)-2-phenylcyclopropyl)cyclobutane-1,3-diamine;-   (trans)-N1-((1S,2R)-2-phenylcyclopropyl)cyclobutane-1,3-diamine;-   (cis)-N1-((1S,2R)-2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1,4-diamine;-   (trans)-N1-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1,4-diamine;-   (cis)-N1-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1,4-diamine;-   (trans)-N1-((1S,2R)-2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1,4-diamine;-   (cis)-N1-((1S,2R)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine;-   (trans)-N1-((1R,2S)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine;-   (cis)-N1-((1R,2S)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine;-   (trans)-N1-((1S,2R)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine;-   (cis)-N1-((1S,2R)-2-(4-(1H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;-   (trans)-N1-((1R,2S)-2-(4-(1H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;-   (cis)-N1-((1R,2S)-2-(4-(1H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;-   (trans)-N1-((1S,2R)-2-(4-(1H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine;-   N-(4′-((1R,2S)-2-(((cis)-4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)piperazine-1-sulfonamide;-   N-(4′-((1S,2R)-2-(((trans)-4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)piperazine-1-sulfonamide;-   N-(4′-((1S,2R)-2-(((cis)-4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)piperazine-1-sulfonamide;-   N-(4′-((1R,2S)-2-(((trans)-4-aminocyclohexyl)amino)cyclo    propyl)-[1,1′-biphenyl]-3-yl)piperazine-1-sulfonamide;-   (cis)-N1-((1S,2R)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine;-   (trans)-N1-((1R,2S)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine;-   (cis)-N1-((R,2S)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine;-   (trans)-N1-((1S,2R)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine;    as well as salts and solvates thereof (including pharmaceutically    acceptable salts and solvates thereof).

The invention also relates to any one or any subgroup of the compoundslisted above. The invention likewise relates to a pharmaceuticallyacceptable salt, preferably a hydrochloride salt (such as, e.g., amonohydrochloride salt, a dihydrochloride salt or, where applicable, atrihydrochloride salt), of any of the compounds listed above.

Preferred embodiments of the compounds of Formula I, Ia, Ia-1, Ib and Icfor use in the compositions and methods of the invention are as definedherein above.

In a further aspect, the invention provides a method for identifying acompound which is a selective inhibitor of LSD1, the method comprisingselecting or providing a compound of Formula I, Ia, Ia-1, Ib or Ic anddetermining the ability of the said compound to inhibit LSD1 and MAO-Aand/or MAO-B using assays such as the ones disclosed in more detaillater on, wherein a compound that inhibits LSD1 to a greater extent thanMAO-A and/or MAO-B is identified as a LSD1 selective inhibitor. LSD1selective inhibitors have IC50 values for LSD1 which are lower than theIC50 value for MAO-A and/or MAO-B. Preferably, the IC50 values for LSD1are two-fold lower than for MAO-A and/or MAO-B. In one aspect of thisembodiment, the LSD1 IC50 value is at least 5-fold lower than the IC50value for MAO-A and/or MAO-B. In one aspect of this embodiment, the LSD1IC50 value is at least 10-fold lower than the IC50 value for MAO-Aand/or MAO-B. Preferably, a selective LSD1 inhibitor exhibits an IC50value for LSD1 that is >50-fold, preferably >100-fold lower than theIC50 value for MAO-A and/or MAO-B.

Asymmetric centers exist in the compounds of formula I, Ia, Ia-1, Ib andIc disclosed herein. It should be understood that the inventionencompasses all individual stereochemical isomeric forms of a compoundof formula I, Ia, Ia-1, Ib and Ic, including diastereomeric,enantiomeric, and epimeric forms, as well as d-isomers and I-isomers((+)-isomers and (−)-isomers), and any mixtures thereof, includingwholly or partially equilibrated mixtures. Individual stereoisomers ofcompounds of the invention can be prepared synthetically fromcommercially available chiral starting materials or by separation frommixtures of stereoisomers, as also shown in the Examples. Methods ofseparation of enantiomeric and diastereomeric mixtures are well known toone skilled in the art. For example, mixtures of diastereomers can beseparated by conventional separation techniques such asrecrystallization or chromatography. Mixtures of enantiomeric productscan be separated by conversion to a mixture of diastereomers followed byseparation using recrystallization or chromatographic techniques, directseparation of enantiomers on chiral chromatographic columns, or anyother appropriate method of chiral resolution known in the art. Startingcompounds of particular stereochemistry are either commerciallyavailable or can be made and resolved by techniques known in the art.

Additionally, the compounds disclosed herein may exist as geometricisomers. The present invention includes all cis, trans, syn, anti,entgegen (E), and zusammen (Z) isomers as well as the mixtures thereof.

Additionally, compounds may exist as tautomers; all tautomeric isomersare provided by this invention.

The compounds of the invention contain one or more basic nitrogen atomsand may therefore form salts with organic or inorganic acids. Thecompounds of the invention may also contain one or more acidic protonsand therefore they may also form salts with bases. There is nolimitation on the type of salt that can be used provided that these arepharmaceutically acceptable when used for therapeutic purposes. Thesalts of a compound of the invention can be obtained during the finalisolation and purification of the compounds of the invention or can beobtained by treating a compound of formula I, Ia, Ia-1, Ib or Ic with asufficient amount of the desired acid or base to give the correspondingsalt in a conventional manner. All salts of the compounds of formula I,Ia, Ia-1, Ib and Ic, including pharmaceutically acceptable salts, areincluded within the scope of the invention. In one embodiment, acompound of formula I, Ia, Ia-1, Ib or Ic is provided in the form of asalt. In a more preferred embodiment, a compound of formula I, Ia andIa-1 is provided in the form of a pharmaceutically acceptable salt. Inone embodiment, such pharmaceutically acceptable salt is ahydrochloride, for example a monohydrochloride, a dihydrochloride or atrihydrochloride.

Additionally, the compounds disclosed herein can exist in unsolvated aswell as solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like. Solvated forms with water are known ashydrates. In general, the solvated forms are considered equivalent tothe unsolvated forms. The invention thus relates to the unsolvated andsolvated forms of the compounds of formula I, Ia, Ia-1, Ib or Ic (or ofany salt thereof).

The compounds of formula I, Ia, Ia-1, Ib and Ic may exist in differentphysical forms, i.e. amorphous and crystalline forms. Moreover, thecompounds of the invention may have the ability to crystallize in morethan one form, a characteristic which is known as polymorphism.Polymorphs can be distinguished by various physical properties wellknown in the art such as X-ray diffraction pattern, melting point orsolubility. All physical forms of the compounds of the invention,including all polymorphic forms (also known as polymorphs) thereof, areincluded within the scope of the invention.

The present invention further covers all unlabeled and isotopicallylabeled forms of the compounds of formula I, Ia, Ia-1, Ib and Ic. In oneembodiment, the invention relates to deuterated forms of the compoundsof formula I, Ia, Ia-1, Ib and Ic.

The invention also relates to a compound of Formula I, Ia, Ia-1, Ib orIc (preferably a compound of formula I, Ia, or Ia-1, more preferably acompound of formula Ia or Ia-1, and most preferably a compound offormula Ia-1) as described and defined herein, wherein the substituents-A-B and —NH-D on the cyclopropyl moiety are in trans-configuration andfurther wherein the compound is optically active. As used herein, theterm “optically active” refers to the ability of a compound to rotateplane polarized light.

The invention, in another aspect, relates to a substantially pure,optically active stereoisomer of a compound of Formula I, Ia, Ia-1, Ibor Ic as described and defined herein, wherein the substituents -A-B and—NH-D on the cyclopropyl moiety are in trans-configuration, or apharmaceutically acceptable salt or solvate thereof, as well as its useas a medicament. As used herein, “substantially pure” means that thereis 90 mole-% or greater of the desired stereoisomer and 10 mole-% orless of any other stereoisomer, preferably that there is 95 mole-% orgreater of the desired stereoisomer and 5 mole-% or less of any otherstereoisomer, more preferably, that there is 98 mole-% or greater of thedesired stereoisomer and 2 mole-% or less of any other stereoisomer,still more preferably, that there is 99 mole-% or greater of the desiredstereoisomer and 1 mole-% or less of any other stereoisomer, and evenmore preferably that there is 99.5 mole-% or greater of the desiredstereoisomer and 0.5 mole-% or less of any other stereoisomer. Thesubstantially pure, optically active stereoisomer of a compound ofFormula I, Ia, Ia-1, Ib or Ic as described and defined herein, whereinthe substituents -A-B and —NH-D on the cyclopropyl moiety are intrans-configuration, is useful in treating or preventing a disease ordisorder, particularly cancer, a neurological disease, or a viralinfection.

Definitions

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group cyclylC₁₋₈ alkyl wouldrepresent a cyclyl group attached to the parent molecule through a C₁₋₈alkyl group.

As used herein, the term “acyl” refers to a carbonyl attached to analkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, or any othermoiety where the atom attached to the carbonyl is carbon. Preferably,the term “acyl” refers to a group of formula —C(═O)R″, wherein R″represents alkenyl, alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl.An “acetyl” group refers to a —C(═O)CH₃ group. An “alkylcarbonyl” or“alkanoyl” group refers to an alkyl group attached to the parentmolecular moiety through a carbonyl group. Examples of such groupsinclude, but are not limited to, methylcarbonyl or ethylcarbonyl.Examples of acyl groups include, but are not limited to, formyl,alkanoyl or aroyl.

As used herein, the term “alkenyl” refers to a straight-chain orbranched-chain hydrocarbon group having one or more double bonds andcontaining from 2 to 20 carbon atoms. A C₂₋₈ alkenyl is an alkenyl grouphaving from 2 to 8 carbon atoms.

As used herein, the term “alkoxy” refers to an alkyl ether group (ie agroup of formula alkyl-O—), wherein the term alkyl is as defined below.Examples of suitable alkyl ether groups include, but are not limited to,methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy,sec-butoxy, tert-butoxy, or n-pentoxy. The term C_(1-z) alkoxy refers toan alkoxy group wherein the alkyl moiety has from 1 to z carbon atoms;for example a C₁₋₈ alkoxy is an alkoxy group wherein the alkyl moiety isC₁₋₈ alkyl, i.e. a group of formula C₁₋₈ alkyl-O—.

As used herein, the term “alkyl” refers to a straight-chain orbranched-chain alkyl group containing from 1 to 20 carbon atoms. AC_(1-z) alkyl is an alkyl from 1 to z carbon atoms; thus, a C₁₋₈ alkylhas from 1 to 8 carbon atoms, a C₁₋₄ alkyl has from 1 to 4 carbon atomsand a C₁₋₂ alkyl has from 1 to 2 carbon atoms. Examples of alkyl groupsinclude, but are not limited to, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neo-pentyl,iso-amyl, hexyl, heptyl, octyl, or nonyl.

As used herein, the term “C₁₋₄ alkylene” refers to an C₁₋₄ alkyl groupattached at two positions, i.e. an alkanediyl group. Examples include,but are not limited to, methylene (i.e. a group of formula —CH₂—),ethylene (including ethane-1,2-diyl and ethane-1,1-diyl), propylene(e.g. propane-1,3-diyl, propane-1,2-diyl and propane-1,1-diyl) andbutylene (e.g. butane-1,4-diyl, butane-1,3-diyl or butane-1,1-diyl).Accordingly, the term “C₁₋₄ alkylene” may refer to a straight-chain orbranched-chain alkylene group having from 1 to 4 carbon atoms.

As used herein, the term “alkynyl” refers to a straight-chain orbranched-chain hydrocarbon group having one or more triple bonds andcontaining from 2 to 20 carbon atoms. A C₂₋₈ alkynyl has from 2 to 8carbon atoms. Examples of alkynyl groups include, but are not limitedto, ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl,pentyn-1-yl, 3-methylbutyn-1-yl, or hexyn-2-yl.

As used herein, the term “amido” refers to an amino group as describedbelow attached to the parent molecular moiety through a carbonyl group(e.g., —C(═O)NRR′), or vice versa (—N(R)C(═O)R′). “Amido” encompasses“C-amido” and “N-amido” as defined herein. R and R′ are as definedherein.

As used herein, the term “C-amido” refers to a —C(═O)NRR′ group with Rand R′ as defined herein.

As used herein, the term “N-amido” refers to a —N(R)C(═O)′ group with Rand R′ as defined herein.

As used herein, the term “amino” refers to —NRR′, wherein R and R′ areindependently selected from the group consisting of hydrogen, alkyl,heteroalkyl, aryl, carbocyclyl, and heterocyclyl. Additionally, R and R′may be combined to form a heterocyclyl. Exemplary “amino” groupsinclude, without being limited thereto, —NH₂, —NH(C₁₋₄ alkyl) and—N(C₁₋₄ alkyl)(C₁₋₄ alkyl).

As used herein, the term “aryl” refers to a carbocyclic aromatic systemcontaining one ring, or two or three rings fused together where in thering atoms are all carbon. The term “aryl” groups includes, but is notlimited to groups such as phenyl, naphthyl, or anthracenyl. The term“monocyclic aryl” refers to phenyl.

As used herein, the term “aryloxy” refers to an aryl group attached tothe parent molecular moiety through an oxy (—O—).

As used herein, the term “carbamate” refers to an O-carbamyl orN-carbamyl group as defined herein. An N-carbamyl group refers to—NR—COOR′, wherein R and R′ are as defined herein. An O-carbamyl grouprefers to —OCO—NRR′, wherein R and R′ are as defined herein.

As used herein, the term “carbonyl” when alone includes formyl —C(═O)Hand in combination is a —C(═O)— group.

As used herein, the term “carboxyl” or “carboxy” refers to —C(═O)OH orthe corresponding “carboxylate” anion, such as is in a carboxylic acidsalt.

An “O-carboxy” group refers to a RC(═O)O— group, where R is as definedherein.

A “C-carboxy” group refers to a —C(═O)OR groups where R is as definedherein.

As used herein, the term “cyano” refers to —CN.

As used herein, the term “carbocyclyl” refers to a saturated orpartially saturated monocyclic or a fused bicyclic or tricyclic groupwherein the ring atoms of the cyclic system are all carbon and whereineach cyclic moiety contains from 3 to 12 carbon atom ring members.“Carbocyclyl” encompasses benzo fused to a carbocyclyl ring system. Onegroup of carbocyclyls have from 5 to 7 carbon atoms. Examples ofcarbocyclyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl,indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, or adamantyl.

As used herein, the term “cycloalkyl”, unless otherwise specified (asfor example in the definition of ring D), refers to a saturatedmonocyclic, bicyclic or tricyclic group wherein the ring atoms of thecyclic system are all carbon and wherein each cyclic moiety containsfrom 3 to 12 carbon atom ring members. A C₃₋₆ cycloalkyl is a cycloalkylthat has from 3 to 6 carbon atoms, i.e. cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. A cycloalkyl containing from 4 to 7 C atomsincludes cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Examplesof cycloalkyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl.

As used herein, the term “cyclyl” refers to an aryl, heterocyclyl, orcarbocyclyl group as defined herein.

As used herein, the term “cyclylC₁₋₈ alkyl” refers to a C₁₋₈ alkyl asdefined above wherein one hydrogen atom in the C₁₋₈ alkyl group has beenreplaced with one cyclyl group as defined above.

As used herein, the term “halo” or “halogen” refers to fluorine,chlorine, bromine, or iodine.

As used herein, the term “haloalkoxy” refers to a haloalkyl group (asdefined below) attached to the parent molecular moiety through an oxygenatom. A haloC₁₋₈ alkoxy group refers to a haloalkoxy group wherein thehaloalkyl moiety has from 1 to 8 C atoms. Examples of haloalkoxy groupsinclude, but are not limited to, trifluoromethoxy, 2-fluoroethoxy,pentafluoroethoxy, or 3-chloropropoxy.

As used herein, the term “haloalkyl” refers to an alkyl group having themeaning as defined above wherein one or more hydrogens are replaced witha halogen. A haloC₁₋₈ alkyl group refers to a haloalkyl group whereinthe alkyl moiety has from 1 to 8 C atoms. Specifically embraced aremonohaloalkyl, dihaloalkyl or polyhaloalkyl groups. A monohaloalkylgroup, for one example, may have an iodo, bromo, chloro or fluoro atomwithin the group. Dihalo or polyhaloalkyl groups may have two or more ofthe same halo atoms or a combination of different halo groups. Examplesof haloalkyl groups include, but are not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl or dichloropropyl.

As used herein, the term “heteroalkyl” refers to a straight or branchedalkyl chain, wherein one, two, or three carbons forming the alkyl chainare each replaced by a heteroatom independently selected from the groupconsisting of O, N, and S, and wherein the nitrogen and/or sulfurheteroatom(s) (if present) may optionally be oxidized and the nitrogenheteroatom(s) (if present) may optionally be quaternized. Theheteroatom(s) O, N and S may, for example, be placed at the end(s) or atan interior position of the heteroalkyl group, i.e., the heteroalkyl maybe bound to the remainder of the molecule via a heteroatom or a carbonatom. Up to two heteroatoms may be consecutive, such as, for example,—CH₂—NH—OCH₃. Accordingly, a further example for a “heteroalkyl” groupis a straight or branched alkyl group, in which two consecutive carbonatoms are replaced by the heteroatoms S and N, respectively, and thesulfur heteroatom is furthermore oxidized, resulting in moieties suchas, e.g., —S(═O)₂—NH₂, —S(═O)₂—NH(alkyl) or —S(═O)₂—N(alkyl)(alkyl).

As used herein, the term “heteroC₁₋₄ alkylene” refers to a straight orbranched C₁₋₄ alkylene group (i.e., a straight or branched C₁₋₄alkanediyl group) linked to one heteroatom selected from O, N and S andalso refers to a straight or branched C₁₋₄ alkylene group wherein one ormore (e.g., 1, 2 (if present) or 3 (if present)) of the carbon atoms ofsaid alkylene group are each replaced by a heteroatom independentlyselected from O, N or S. The nitrogen and/or sulfur heteroatom(s) (ifpresent) may optionally be oxidized and the nitrogen heteroatom(s) (ifpresent) may optionally be quaternized. The heteroatom(s) O, N and S maybe placed at the end(s) and/or at an interior position of the heteroC₁₋₄alkylene group. It is to be understood that the presence of hydrogenatoms will depend on the valence of the heteroatom replacing therespective carbon atom. If, for example, the carbon atom in a —CH₂—group is replaced by O or S, the resulting group will be —O— or —S—,respectively, while it will be —N(H)— when the carbon atom is replacedby N. Likewise, if the central carbon atom in a group —CH₂—CH(—CH₃)—CH₂—is replaced by N, the resulting group will be —CH₂—N(—CH₃)—CH₂—. Anexample for a “heteroC₁₋₄ alkylene” group is a straight or branched C₁₋₄alkylene group, in which two consecutive carbon atoms are replaced bythe heteroatoms S and N, respectively, and the sulfur heteroatom isfurthermore oxidized, resulting in moieties such as, e.g., —S(═O)₂—N(H)—or —S(═O)₂—N(CH₃)—.

As used herein, the term “heteroaryl” refers to a 5 to 6 memberedunsaturated monocyclic ring, or a fused bicyclic or tricyclic ringsystem in which the rings are aromatic and in which at least one ringcontains at least one heteroatom selected from the group consisting ofO, S, and N. Preferred heteroaryl groups are 5- to 6-membered monocyclicor 9- to 10-membered bicyclic heteroaryl groups. Examples of heteroarylgroups include, but are not limited to, pyridinyl, imidazolyl,imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl,oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl,quinazolinyl, quinoxalinyl, naphthyridinyl, or furopyridinyl.

As used herein, the term “heterocyclyl” or “heterocycle” each refer to asaturated, partially unsaturated, or fully unsaturated monocyclic,bicyclic, or tricyclic heterocyclic group containing at least oneheteroatom as a ring member, wherein each said heteroatom may beindependently selected from the group consisting of nitrogen, oxygen,and sulfur wherein the nitrogen or sulfur atoms may be oxidized (e.g.,—N═O, —S(═O)—, or —S(═O)₂—). Additionally, 1, 2, or 3 of the carbonatoms of the heterocyclyl may be optionally oxidized (e.g., to give anoxo group or ═O). One group of heterocyclyls has from 1 to 4 heteroatomsas ring members. Another group of heterocyclyls has from 1 to 2heteroatoms as ring members. One group of heterocyclyls has from 3 to 8ring members in each ring. Yet another group of heterocyclyls has from 3to 7 ring members in each ring. Again another group of heterocyclyls hasfrom 5 to 6 ring members in each ring. “Heterocyclyl” is intended toencompass a heterocyclyl group fused to a carbocyclyl or benzo ringsystems. Examples of heterocyclyl groups include, but are not limitedto, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino,morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinylimidazolinyl, or imidazolidinyl. Examplesof heteroaryls that are heterocyclyls include, but are not limited to,pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl,isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl,indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl,isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl,thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, or furopyridinyl.

As used herein, the term “heterocycloalkyl” refers to a heterocyclylgroup that is not fully unsaturated e.g., one or more of the ringssystems of a heterocycloalkyl is not aromatic. Examples ofheterocycloalkyls include piperazinyl, morpholinyl, piperidinyl, orpyrrolidinyl.

As used herein, the term “hydroxyl” or “hydroxy” refers to —OH.

As used herein, the term “hydroxyC₁₋₈ alkyl” refers to an C₁₋₈ alkylgroup, wherein one or more hydrogen atoms (preferably one or two) havebeen replaced by hydroxy groups.

As used herein, the term “R¹²R¹³N—C₁₋₈ alkyl” refers to an C₁₋₈ alkylgroup, wherein one or more hydrogen atoms (preferably one or two, morepreferably one) have been replaced by —NR¹²R¹³.

As used herein, the term “lower” where not otherwise specificallydefined, means containing from 1 to and including 6 carbon atoms.

As used herein, the term “nitro” refers to —NO₂.

As used herein, the terms “sulfonate” “sulfonic acid” and “sulfonic”refer to the —SO₃H group and its anion as the sulfonic acid is used insalt formation.

As used herein, the term “sulfinyl” refers to —S(═O)(R), with R asdefined herein.

As used herein, the term “sulfonyl” refers to —S(═O)₂R, with R asdefined herein.

As used herein, the term “sulfonamide” refers to an N-sulfonamido orS-sulfonamido group as defined herein.

As used herein, the term “N-sulfonamido” refers to a RS(═O)₂N(R′)— groupwith R and R′ as defined herein. Preferred N-sulfonamido groups are—NHSO₂R, wherein R is as defined herein, preferably R is alkyl,cycloalkyl, heteroalkyl, aryl, heteroaryl or heterocycloalkyl, morepreferably R is alkyl, aryl, heteroaryl or heterocycloalkyl, whereinsaid alkyl, said cycloalkyl, said heteroalkyl, said aryl, saidheteroaryl and said heterocycloalkyl are each optionally substituted.The optional substituents on said alkyl, said cycloalkyl, saidheteroalkyl, said aryl, said heteroaryl and said heterocycloalkyl may beselected independently from lower alkyl, lower alkenyl, lower alkynyl,lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lowerhaloalkyl, lower cycloalkyl, phenyl, aryl, heteroaryl, pyridyl, aryloxy,lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl,lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano,halogen, hydroxyl, amino, amido, nitro, thiol, lower alkylthio, lowerhaloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonicacid, trisubstituted silyl, N₃, SH, SCH₃, C(O)CH₃, CO₂CH₃, CO₂H,carbamate, and urea. Preferably, the optional substituents areindependently selected from hydroxyl, halo, alkyl, alkoxy, haloalkyl,haloalkoxy, —N(C₁₋₃ alkyl)₂, —NH(C₁₋₃ alkyl), —NHC(═O)(C₁₋₃ alkyl),—C(═O)OH, —C(═O)O(C₁₋₃ alkyl), —C(═O)(C₁₋₃ alkyl), —C(═O)NH₂,—C(═O)NH(C₁₋₃ alkyl), —C(═O)NH(cycloalkyl), —C(═O)N(C₁₋₃ alkyl)₂,—S(═O)₂(C₁₋₃ alkyl), —S(═O)₂NH₂, —S(═O)₂N(C₁₋₃ alkyl)₂, —S(═O)₂NH(C₁₋₃alkyl), —CHF₂, —OCF₃, —OCHF₂, —SCF₃, —CF₃, —CN, —NH₂, —NO₂, ortetrazolyl. Particularly preferred N-sulfonamido groups are —NHSO₂R,wherein R is alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl orheterocycloalkyl, and preferably R is alkyl, aryl, heteroaryl orheterocycloalkyl, and —NHSO₂ (optionally substituted aryl). Still morepreferred N-sulfonamido groups are —NHSO₂alkyl and —NHSO₂ (optionallysubstituted aryl). Exemplary, non-limiting N-sulfonamido groups are—NHSO₂alkyl such as —NHSO₂CH₃, —NHSO₂CH₂CH₃ or —NHSO₂ (isopropyl), and—NHSO₂ (optionally substituted aryl) such as —NHSO₂-phenyl,—NHSO₂-(2-cyanophenyl), —NHSO₂-(3-cyanophenyl), —NHSO₂-(4-cyanophenyl),—NHSO₂-(2-aminophenyl), —NHSO₂-(3-aminophenyl) or—NHSO₂-(4-aminophenyl). Other exemplary N-sulfonamido groups are —NHSO₂(optionally substituted heterocycloalkyl) such as—NHSO₂-(piperazin-1-yl) and —NHSO₂ (optionally substituted heteroaryl)such as —NHSO₂-(optionally substituted pyridyl) like —NHSO₂-(3-pyridyl)or —NHSO₂-(6-amino-3-pyridyl).

As used herein, the term “S-sulfonamido” refers to a —S(═O)₂NRR′, group,with R and R′ as defined herein.

As used herein, the term “urea” refers to a —N(R)C(═O)N(R)(R′) groupwherein R and R′ are as defined herein.

The term R or the term R′, appearing by itself and without a numberdesignation, unless otherwise defined, refers to a moiety selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl,heteroaryl and heterocycloalkyl. Both unsubstituted and substitutedforms of the above groups are encompassed. Preferably, said groups areunsubstituted.

Whether an R group has a number designation or not, every R group,including R, R′ and R^(z) where z=(1, 2, 3, . . . z), every substituent,and every term should be understood to be independent of every other interms of selection from a group. Should any variable, substituent, orterm (e.g., aryl, heterocycle, R, etc.) occur more than one time in aformula or generic structure, its definition at each occurrence isindependent of the definition at every other occurrence. Those of skillin the art will further recognize that certain groups may be attached toa parent molecule or may occupy a position in a chain of elements fromeither end as written. Thus, by way of example only, an unsymmetricalgroup such as —C(═O)N(R)— may be attached to the parent moiety at eitherthe carbon or the nitrogen.

As used herein, the term “optionally substituted” means the preceding oranteceding group may be substituted or unsubstituted. When substitutedand unless otherwise specified, the substituents of an “optionallysubstituted” group may include, without limitation, one or moresubstituents independently selected from the following groups or aparticular designated set of groups, alone or in combination: loweralkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl,lower heterocycloalkyl, lower haloalkyl, lower cycloalkyl, phenyl, aryl,heteroaryl, pyridyl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, loweracyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester,lower carboxamido, cyano, halogen, hydroxyl, amino, amido, nitro, thiol,lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio,sulfonate, sulfonic acid, trisubstituted silyl, N₃, SH, SCH₃, C(O)CH₃,CO₂CH₃, CO₂H, carbamate, and urea. Two substituents may be joinedtogether to form a fused five-, six-, or seven-membered carbocyclic orheterocyclic ring consisting of zero to three heteroatoms, for exampleforming methylenedioxy or ethylenedioxy. An optionally substituted groupmay be unsubstituted (e.g., —CH₂CH₃), fully substituted (e.g., —CF₂CF₃),monosubstituted (e.g., —CH₂CH₂F) or substituted at a level anywherein-between fully substituted and monosubstituted (e.g., —CH₂CF₃). Wheresubstituents are recited without qualification as to substitution, bothsubstituted and unsubstituted forms are encompassed. Where a substituentis qualified as “substituted,” the substituted form is specificallyintended. Additionally, different sets of optional substituents to aparticular moiety may be defined as needed; in these cases, the optionalsubstitution will be as defined, often immediately following the phrase,“optionally substituted with.” In one specific definition, the optionalsubstituents are chosen from hydroxyl, halo, alkyl, alkoxy, haloalkyl,haloalkoxy, —N(C₁₋₃ alkyl)₂, —NH(C₁₋₃ alkyl), —NHC(═O)(C₁₋₃ alkyl),—C(═O)OH, —C(═O)O(C₁₋₃ alkyl), —C(═O)(C₁₋₃ alkyl), —C(═O)NH₂,—C(═O)NH(C₁₋₃ alkyl), —C(═O)NH(cycloalkyl), —C(═O)N(C₁₋₃ alkyl)₂,—S(═O)₂(C₁₋₃ alkyl), —S(═O)₂NH₂, —S(═O)₂N(C₁₋₃ alkyl)₂, —S(═O)₂NH(C₁₋₃alkyl), —CHF₂, —OCF₃, —OCHF₂, —SCF₃, —CF₃, —CN, —NH₂, —NO₂, ortetrazolyl.

As used herein, the term “optional substituent” denotes that thecorresponding substituent may be present or may be absent. Accordingly,a compound having 1, 2 or 3 optional substituents may be unsubstitutedor may be substituted with 1, 2 or 3 substituents.

As used herein, the term “treating a disease” refers to a slowing of ora reversal of the progress of the disease. Treating a disease includestreating a symptom and/or reducing the symptoms of the disease.

As used herein, the term “preventing a disease” refers to a slowing ofthe disease or of the onset of the disease or the symptoms thereof.Preventing a disease or disorder can include stopping the onset of thedisease or symptoms thereof.

As used herein, the term “dosage unit” refers to a physically discreteunit, such as a capsule or tablet suitable as a unitary dosage for ahuman patient. Each unit contains a predetermined quantity of a compoundof Formula I which was discovered or believed to produce the desiredpharmacokinetic profile which yields the desired therapeutic effect. Thedosage unit is composed of a compound of Formula I in association withat least one pharmaceutically acceptable carrier, salt, excipient, orcombination thereof.

As used herein, the term “subject” or “patient” or “individual”, such asthe subject in need of treatment or prevention, may be a eukaryote, ananimal, a vertebrate animal, a mammal, a rodent (e.g., a guinea pig, ahamster, a rat, a mouse), a murine (e.g., a mouse), a canine (e.g., adog), a feline (e.g., a cat), an equine (e.g. a horse), a primate, asimian (e.g., a monkey or ape), a monkey (e.g., a marmoset, a baboon),an ape (e.g., gorilla, chimpanzee, orangutan, gibbon), or a human. Themeaning of the terms “eukaryote”, “animal”, “mammal”, etc. is well knownin the art and can, for example, be deduced from Wehner und Gehring(1995; Thieme Verlag). In the context of this invention, it isparticularly envisaged that animals are to be treated which areeconomically, agronomically or scientifically important. Scientificallyimportant organisms include, but are not limited to, mice, rats, andrabbits. Lower organisms such as, e.g., fruit flies like Drosophilamelagonaster and nematodes like Caenorhabditis elegans may also be usedin scientific approaches. Non-limiting examples of agronomicallyimportant animals are sheep, cattle and pig, while, for example, catsand dogs may be considered as economically important animals.Preferably, the subject/patient/individual is a mammal; more preferably,the subject/patient/individual is a human or a non-human mammal (suchas, e.g., a guinea pig, a hamster, a rat, a mouse, a rabbit, a dog, acat, a horse, a monkey, an ape, a marmoset, a baboon, a gorilla, achimpanzee, an orangutan, a gibbon, a sheep, cattle, or a pig); evenmore preferably, the subject/patient/individual is a human.

As used herein, the term “dose” or “dosage” refers to the amount ofactive ingredient that an individual takes or is administered at onetime. For example, a 40 mg dose of a compound of Formula I refers to, inthe case of a twice-daily dosage regimen, a situation where theindividual takes 40 mg of a compound of Formula I twice a day, e.g., 40mg in the morning and 40 mg in the evening. The 40 mg of a compound ofFormula I dose can be divided into two or more dosage units, e.g., two20 mg dosage units of a compound of Formula I in tablet form or two 20mg dosage units of a compound of Formula I in capsule form.

As used herein, the term “therapeutically effective amount”, such as thetherapeutically effective amount of a compound of the present invention,refers to the amount sufficient to produce a desired biological effect(e.g., a therapeutic effect) in a subject. Accordingly, atherapeutically effective amount of a compound may be an amount which issufficient to treat or prevent a disease or disorder, and/or delay theonset or progression of a disease or disorder, and/or alleviate one ormore symptoms of the disease or disorder, when administered to a subjectsuffering from or susceptible to that disease or disorder.

As used herein, a “pharmaceutically acceptable prodrug” is a compoundthat may be converted under physiological conditions or by solvolysis tothe specified compound or to a pharmaceutically acceptable salt of suchcompound.

As used herein, a “pharmaceutically acceptable salt” is intended to meana salt that retains the biological effectiveness of the free acids andbases of the specified compound and that is not biologically orotherwise undesirable. A compound for use in the invention may possess asufficiently acidic, a sufficiently basic, or both functional groups,and accordingly react with any of a number of inorganic or organicbases, and inorganic and organic acids, to form a pharmaceuticallyacceptable salt. Exemplary pharmaceutically acceptable salts includethose salts prepared by reaction of the compounds of the presentinvention with a mineral or organic acid, such as hydrochlorides,hydrobromides, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites,phosphates, monohydrophosphates, dihydrophosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, nitrates, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4 dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates,glycollates, tartrates, methane-sulfonates, ethane-sulfonates,propanesulfonates, benzenesulfonates, toluenesulfonates,trifluoromethansulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, mandelates, pyruvates, stearates, ascorbates,or salicylates. When the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof may includealkali metal salts, e.g. sodium or potassium salts; alkaline earth metalsalts, e.g. calcium or magnesium salts; and salts formed with suitableorganic ligands such as ammonia, alkylamines, hydroxyalkylamines,lysine, arginine, N-methylglucamine, procaine and the like.Pharmaceutically acceptable salts are well known in the art.

As used herein, a “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” refers to a non-API (API refersto Active Pharmaceutical Ingredient) substances such as disintegrators,binders, fillers, and lubricants used in formulating pharmaceuticalproducts. They are generally safe for administering to humans accordingto established governmental standards, including those promulgated bythe United States Food and Drug Administration and the European MedicalAgency. Pharmaceutically acceptable carriers or excipients are wellknown to those skilled in the art.

As is understood by the skilled artisan, certain variables in the listof substituents are repetitive (different name for the samesubstituent), generic to other terms in the list, and/or partiallyoverlap in content with other terms. In the compounds of the invention,the skilled artisan recognizes that substituents may be attached to theremainder of the molecule via a number of positions and the preferredpositions are as illustrated in the Examples.

The compounds of the invention are unexpectedly potent and selectiveinhibitors of LSD1. Avoiding inhibition of “off-targets” can avoidunwanted or undesirable side-effects like the cheese effect associatedwith MAO-A. The compounds of the invention are thus useful for thetreatment or prevention of any disease or disorder associated with LSD1.This includes cancer, neurological diseases and viral infections, amongothers.

Preferably, the compounds of formula I, including compounds of formulaIa, Ia-1, Ib and Ic, as well as any salts and solvates thereof, are usedfor the treatment or prevention of cancer, and most preferably for thetreatment of cancer. Cancers that may be treated (or prevented) with thecompounds of the invention include, but are not limited to cancers suchas:

Hematologic cancers (also designated herein as blood cancers), includingcancers of the blood, bone marrow and lymph nodes such as leukemias(e.g. acute myelogenous leukemia (AML), acute promyelocytic leukemia(APL), chronic myelogenous leukemia (CML), chronic neutrophilicleukemia, chronic eosinophilic leukemia, chronic lymphocytic leukemia(CLL), acute lymphoblastic leukemia (ALL), or hairy cell leukemia),myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome,and lymphomas (e.g. Hodgkin's disease, non-Hodgkin's lymphoma (malignantlymphoma));Breast cancer, including invasive ductal carcinoma, in situ ductalcarcinoma, lobular carcinoma, and mixed ductal and lobular carcinoma;Lung cancer such as bronchogenic carcinoma (e.g. squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,sarcoma, lymphoma, chondromatous hamartoma, and mesothelioma;Gastrointestinal cancers such as esophagus (e.g. squamous cellcarcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (e.g.carcinoma, lymphoma, leiomyosarcoma), pancreas (e.g. ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (e.g. adenocarcinoma, lymphoma, carcinoid tumors,Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma),and large bowel (e.g. adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma);Genitourinary tract cancers such as kidney (e.g. adenocarcinoma, Wilm'stumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (e.g.squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (e.g. adenocarcinoma, sarcoma), and testis (e.g. seminoma,teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma,sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoidtumors, lipoma);Liver cancer such as hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma;Bone cancer such as osteogenic sarcoma (osteosarcoma), fibrosarcoma,malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma,malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignantgiant cell tumor chordoma, osteochronfroma (osteocartilaginousexostoses), benign chondroma, chondroblastoma, chondromyxofibroma,osteoid osteoma and giant cell tumors;Nervous system cancers such as skull (e.g. osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (e.g. meningioma,meningiosarcoma, gliomatosis), brain (e.g. astrocytoma, medulloblastoma,glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, and sarcoma;Gynecological cancers such as uterus (e.g. endometrial carcinoma),cervix (e.g. cervical carcinoma, pre-tumor cervical dysplasia), ovaries(e.g. ovarian carcinoma (serous cystadenocarcinoma, mucinouscystadenocarcinoma, unclassified carcinoma), granulosa-thecal celltumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma),vulva (e.g. squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (e.g. clear cellcarcinoma, squamous cell carcinoma, botryoid sarcoma (embryonalrhabdomyosarcoma)), and fallopian tubes (carcinoma);Cardiac cancer such as sarcoma (e.g. angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma;Skin cancer such as malignant melanoma, basal cell carcinoma, squamouscell carcinoma, and Kaposi's sarcoma; andAdrenal glands cancer such as neuroblastoma.

Accordingly, in one embodiment, the compounds of the invention are usedfor the treatment or prevention of cancer, particularly for thetreatment of cancer, wherein said cancer is chosen from blood cancer,leukemia, lymphoma, breast cancer, lung cancer, prostate cancer,colorectal cancer, brain cancer, neuroblastoma, bladder cancer, livercancer, sarcoma, myeloma and skin cancer. In another embodiment, thecompounds of the invention are used for the treatment or prevention(particularly for the treatment) of blood cancers (also known ashematological cancers), including leukemias (for example, acutemyelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronicneutrophilic leukemia, chronic eosinophilic leukemia, chroniclymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or hairycell leukemia), lymphomas and myelomas, prostate cancer, breast cancer,lung cancer, colorectal cancer, brain cancer or skin cancer. In apreferred embodiment, the compounds of formula I, including compounds offormula Ia, Ia-1, Ib and Ic, are used for the treatment of a bloodcancer. More preferably, the compounds of formula I, including compoundsof formula Ia, Ia-1, Ib and Ic, are used for the treatment of leukemia,including acute myelogenous leukemia (AML), chronic myelogenous leukemia(CML), chronic neutrophilic leukemia, chronic eosinophilic leukemia,chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL),and hairy cell leukemia.

Typically, compounds according to Formula I, Ia, Ia-1, Ib or Ic can beeffective at an amount of from about 0.01 μg/kg to about 100 mg/kg perday based on total body weight. The active ingredient may beadministered at once, or may be divided into a number of smaller dosesto be administered at predetermined intervals of time. The suitabledosage unit for each administration can be, e.g., from about 1 μg toabout 2000 mg, preferably from about 5 μg to about 1000 mg. Even morepreferably, the amount of active ingredient administered is from about 5μg to about 100 mg per day. These doses will depend on thepharmacokinetic parameters of the particular compound and other ADMEproperties as well as the efficacy of the compound in a particulardisease setting.

It should be understood that the dosage ranges set forth above areexemplary only and are not intended to limit the scope of thisinvention. The therapeutically effective amount for each active compoundcan vary with factors including but not limited to the activity of thecompound used, stability of the active compound in the patient's body,the severity of the conditions to be alleviated, the total weight of thepatient treated, the route of administration, the ease of absorption,distribution, and excretion of the active compound by the body, the ageand sensitivity of the patient to be treated, and the like, as will beapparent to a skilled artisan. The amount of administration can beadjusted as the various factors change over time.

While it is possible that a compound of the invention may beadministered for use in therapy directly as such, it is typicallyadministered in the form of a pharmaceutical composition, whichcomprises said compound as active pharmaceutical ingredient togetherwith one or more pharmaceutically acceptable excipients or carriers.

The compounds of the invention may be administered by any means thataccomplish their intended purpose. Examples include administration bythe oral, parenteral, intravenous, subcutaneous or topical routes.

For oral delivery, the active compounds can be incorporated into aformulation that includes pharmaceutically acceptable carriers such asbinders (e.g., gelatin, cellulose, gum tragacanth), excipients (e.g.,starch, lactose), lubricants (e.g., magnesium stearate, silicondioxide), disintegrating agents (e.g., alginate, Primogel, and cornstarch), and sweetening or flavoring agents (e.g., glucose, sucrose,saccharin, methyl salicylate, and peppermint). The formulation can beorally delivered in the form of enclosed gelatin capsules or compressedtablets. Capsules and tablets can be prepared in any conventionaltechniques. The capsules and tablets can also be coated with variouscoatings known in the art to modify the flavors, tastes, colors, andshapes of the capsules and tablets. In addition, liquid carriers such asfatty oil can also be included in capsules.

Suitable oral formulations can also be in the form of suspension, syrup,chewing gum, wafer, elixir, and the like. If desired, conventionalagents for modifying flavors, tastes, colors, and shapes of the specialforms can also be included. In addition, for convenient administrationby enteral feeding tube in patients unable to swallow, the activecompounds can be dissolved in an acceptable lipophilic vegetable oilvehicle such as olive oil, corn oil and safflower oil.

The active compounds can also be administered parenterally in the formof solution or suspension, or in lyophilized form capable of conversioninto a solution or suspension form before use. In such formulations,diluents or pharmaceutically acceptable carriers such as sterile waterand physiological saline buffer can be used. Other conventionalsolvents, pH buffers, stabilizers, anti-bacteria agents, surfactants,and antioxidants can all be included. For example, useful componentsinclude sodium chloride, acetates, citrates or phosphates buffers,glycerin, dextrose, fixed oils, methyl parabens, polyethylene glycol,propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, andthe like. The parenteral formulations can be stored in any conventionalcontainers such as vials and ampoules.

Routes of topical administration include nasal, bucal, mucosal, rectal,or vaginal applications. For topical administration, the activecompounds can be formulated into lotions, creams, ointments, gels,powders, pastes, sprays, suspensions, drops and aerosols. Thus, one ormore thickening agents, humectants, and stabilizing agents can beincluded in the formulations. Examples of such agents include, but arenot limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum,beeswax, or mineral oil, lanolin, squalene, and the like. A special formof topical administration is delivery by a transdermal patch. Methodsfor preparing transdermal patches are disclosed, e.g., in Brown, et al.(1988) Ann. Rev. Med. 39:221-229 which is incorporated herein byreference.

Subcutaneous implantation for sustained release of the active compoundsmay also be a suitable route of administration. This entails surgicalprocedures for implanting an active compound in any suitable formulationinto a subcutaneous space, e.g., beneath the anterior abdominal wall.See, e.g., Wilson et al. (1984) J. Clin. Psych. 45:242-247. Hydrogelscan be used as a carrier for the sustained release of the activecompounds. Hydrogels are generally known in the art. They are typicallymade by crosslinking high molecular weight biocompatible polymers into anetwork, which swells in water to form a gel like material. Preferably,hydrogels are biodegradable or biosorbable. For purposes of thisinvention, hydrogels made of polyethylene glycols, collagen, orpoly(glycolic-co-L-lactic acid) may be useful. See, e.g., Phillips etal. (1984) J. Pharmaceut. Sci., 73: 1718-1720.

The active compounds can also be conjugated, to a water solublenon-immunogenic non-peptidic high molecular weight polymer to form apolymer conjugate. For example, an active compound is covalently linkedto polyethylene glycol to form a conjugate. Typically, such a conjugateexhibits improved solubility, stability, and reduced toxicity andimmunogenicity. Thus, when administered to a patient, the activecompound in the conjugate can have a longer half-life in the body, andexhibit better efficacy. See generally, Burnham (1994) Am. J. Hosp.Pharm. 15:210-218. PEGylated proteins are currently being used inprotein replacement therapies and for other therapeutic uses. Forexample, PEGylated interferon (PEG-INTRON A®) is clinically used fortreating Hepatitis B. PEGylated adenosine deaminase (ADAGEN®) is beingused to treat severe combined immunodeficiency disease (SCIDS).PEGylated L-asparaginase (ONCAPSPAR®) is being used to treat acutelymphoblastic leukemia (ALL). It is preferred that the covalent linkagebetween the polymer and the active compound and/or the polymer itself ishydrolytically degradable under physiological conditions. Suchconjugates known as “prodrugs” can readily release the active compoundinside the body. Controlled release of an active compound can also beachieved by incorporating the active ingredient into microcapsules,nanocapsules, or hydrogels generally known in the art. Otherpharmaceutically acceptable prodrugs of the compounds of this inventioninclude, but are not limited to, esters, carbonates, thiocarbonates,N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivativesof tertiary amines, N-Mannich bases, Schiff bases, amino acidconjugates, phosphate esters, metal salts and sulfonate esters.

Liposomes can also be used as carriers for the active compounds of thepresent invention. Liposomes are micelles made of various lipids such ascholesterol, phospholipids, fatty acids, and derivatives thereof.Various modified lipids can also be used. Liposomes can reduce thetoxicity of the active compounds, and increase their stability. Methodsfor preparing liposomal suspensions containing active ingredientstherein are generally known in the art. See, e.g., U.S. Pat. No.4,522,811; Prescott, Ed., Methods in Cell Biology, Volume XIV, AcademicPress, New York, N.Y. (1976).

The active compounds can also be administered in combination withanother active agent that synergistically treats or prevents the samesymptoms or is effective for another disease or symptom in the patienttreated so long as the other active agent does not interfere with oradversely affect the effects of the active compounds of this invention.Such other active agents include but are not limited toanti-inflammatory agents, antiviral agents, antibiotics, antifungalagents, antithrombotic agents, cardiovascular drugs, cholesterollowering agents, anti-cancer drugs, hypertension drugs, and the like.

Combination therapy includes administration of a single pharmaceuticaldosage formulation which contains a compound of the invention and one ormore additional active agents, as well as administration of the compoundof the invention and each additional active agent in its own separatepharmaceutical dosage formulation. If administered separately, theadministration can be simultaneous, sequential or separate, and thecompound of the invention and the additional therapeutic agent(s) can beadministered via the same administration route or using differentadministration routes, for example one compound can be administeredorally and the other intravenously.

In particular, when a compound of formula I, Ia, Ia-1, Ib or Ic is usedfor the treatment or prevention of cancer, said compound can beadministered in combination with one or more further agents known to beuseful in the treatment or prevention of cancer, including chemotherapyor radiotherapy.

Typically, for combination therapy with a compound of the invention anyantineoplastic agent that has activity versus a cancer being treated orprevented with a compound of the invention may be used. Examples ofantineoplastic agents that can be used in combination with the compoundsand methods of the present invention include, in general, and asappropriate, alkylating agents, anti-metabolites, epidophyllotoxins,antineoplastic enzymes, topoisomerase inhibitors, procarbazines,mitoxantrones, platinum coordination complexes, biological responsemodifiers and growth inhibitors, hormonal/anti-hormonal therapeuticagents and haematopoietic growth factors. Exemplary classes ofantineoplastic agents include the anthracyclines, vinca drugs,mitomycins, bleomycins, cytotoxic nucleosides, epothilones,discodermolides, pteridines, diynenes and podophyllotoxins. Particularlyuseful members of those classes include, for example, carminomycin,daunorubicin, aminopterin, methotrexate, methopterin,dichloromethotrexate, mitomycin C, porfiromycin, 5-fluorouracil,6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin orpodo-phyllotoxin derivatives such as etoposide, etoposide phosphate orteniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine,leurosine, paclitaxel and the like. Other useful antineoplastic agentsinclude estramustine, carboplatin, cyclophosphamide, bleomycin,gemcitibine, ifosamide, melphalan, hexamethyl melamine, thiotepa,cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase,camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide,leuprolide, pyridobenzoindole derivatives, interferons and interleukins.

Thus, a compound of formula I, Ia, Ia-1, Ib or Ic according to thepresent invention can be used for the treatment or prevention of cancer,wherein said compound is to be administered in combination with one ormore antineoplastic agents. The antineoplastic agents to be administeredfor combination therapy may be selected, as appropriate, from: a tumorangiogenesis inhibitor (for example, a protease inhibitor, an epidermalgrowth factor receptor kinase inhibitor, or a vascular endothelialgrowth factor receptor kinase inhibitor); a cytotoxic drug (for example,an antimetabolite, such as purine and pyrimidine analogantimetabolites); an antimitotic agent (for example, a microtubulestabilizing drug or an antimitotic alkaloid); a platinum coordinationcomplex; an anti-tumor antibiotic; an alkylating agent (for example, anitrogen mustard or a nitrosourea); an endocrine agent (for example, anadrenocorticosteroid, an androgen, an anti-androgen, an estrogen, ananti-estrogen, an aromatase inhibitor, a gonadotropin-releasing hormoneagonist, or a somatostatin analog); or a compound that targets an enzymeor receptor that is overexpressed and/or otherwise involved in aspecific metabolic pathway that is misregulated in the tumor cell (forexample, ATP and GTP phosphodiesterase inhibitors, histone deacetylaseinhibitors, protein kinase inhibitors (such as serine, threonine andtyrosine kinase inhibitors (for example, Abelson protein tyrosinekinase)) and the various growth factors, their receptors and kinaseinhibitors therefor (such as epidermal growth factor receptor kinaseinhibitors, vascular endothelial growth factor receptor kinaseinhibitors, fibroblast growth factor inhibitors, insulin-like growthfactor receptor inhibitors and platelet-derived growth factor receptorkinase inhibitors)); aminopeptidase inhibitors; proteasome inhibitors;cyclooxygenase inhibitors (for example, cyclooxygenase-1 orcyclooxygenase-2 inhibitors); topoisomerase inhibitors (for example,topoisomerase I inhibitors or topoisomerase II inhibitors); or retinoidagents.

An alkylating agent which can be used as an antineoplastic agent incombination with a compound of the present invention may be, forexample, a nitrogen mustard (such as cyclophosphamide, mechlorethamine(chlormethine), uramustine, melphalan, chlorambucil, ifosfamide,bendamustine, or trofosfamide), a nitrosourea (such as carmustine,streptozocin, fotemustine, lomustine, nimustine, prednimustine,ranimustine, or semustine), an alkyl sulfonate (such as busulfan,mannosulfan, or treosulfan), an aziridine (such as hexamethylmelamine(altretamine), triethylenemelamine, ThioTEPA(N,N′N′-triethylenethiophosphoramide), carboquone, or triaziquone), ahydrazine (such as procarbazine), a triazene (such as dacarbazine), oran imidazotetrazines (such as temozolomide).

A platinum coordination complex which can be used as an antineoplasticagent in combination with a compound of the present invention may be,for example, cisplatin, carboplatin, nedaplatin, oxaliplatin,satraplatin, or triplatin tetranitrate.

A cytotoxic drug which can be used as an antineoplastic agent incombination with a compound of the present invention may be, forexample, an antimetabolite, including folic acid analog antimetabolites(such as aminopterin, methotrexate, pemetrexed, or raltitrexed), purineanalog antimetabolites (such as cladribine, clofarabine, fludarabine,6-mercaptopurine (including its prodrug form azathioprine), pentostatin,or 6-thioguanine), and pyrimidine analog antimetabolites (such ascytarabine, decitabine, azacytidine, 5-fluorouracil (including itsprodrug forms capecitabine and tegafur), floxuridine, gemcitabine,enocitabine, or sapacitabine).

An antimitotic agent which can be used as an antineoplastic agent incombination with a compound of the present invention may be, forexample, a taxane (such as docetaxel, larotaxel, ortataxel,paclitaxel/taxol, or tesetaxel), a Vinca alkaloid (such as vinblastine,vincristine, vinflunine, vindesine, vinzolidine, or vinorelbine), anepothilone (such as epothilone A, epothilone B, epothilone C, epothiloneD, epothilone E, or epothilone F) or an epothilone B analog (such asixabepilone/azaepothilone B).

An anti-tumor antibiotic which can be used as an antineoplastic agent incombination with a compound of the present invention may be, forexample, an anthracycline (such as aclarubicin, daunorubicin,doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin,or zorubicin), an anthracenedione (such as mitoxantrone, or pixantrone)or an anti-tumor antibiotic isolated from Streptomyces (such asactinomycin (including actinomycin D), bleomycin, mitomycin (includingmitomycin C), or plicamycin).

A tyrosine kinase inhibitor which can be used as an antineoplastic agentin combination with a compound of the present invention may be, forexample, axitinib, bosutinib, cediranib, dasatinib, erlotinib,gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib,sorafenib, sunitinib, or vandetanib.

A topoisomerase-inhibitor which can be used as an antineoplastic agentin combination with a compound of the present invention may be, forexample, a topoisomerase I inhibitor (such as irinotecan, topotecan,camptothecin, belotecan, rubitecan, or lamellarin D) or a topoisomeraseII inhibitor (such as amsacrine, etoposide, etoposide phosphate,teniposide, or doxorubicin).

Further antineoplastic agents may be used in combination with a compoundof the present invention. The antineoplastic agents may includebiological or chemical molecules, such as TNF-related apoptosis-inducingligand (TRAIL), tamoxifen, toremifene, fluoxymesterol, raloxifene,diethylstibestrol, bicalutamide, nilutamide, flutamide,aminoglutethimide, anastrozole, tetrazole, luteinizing hormone releasehormone (LHRH) analogues, ketoconazole, goserelin acetate, leuprolide,megestrol acetate, prednisone, mifepristone, amsacrine, bexarotene,estramustine, irofulven, trabectedin, cetuximab, panitumumab,tositumomab, alemtuzumab, bevacizumab, edrecolomab, gemtuzumab,alvocidib, seliciclib, aminolevulinic acid, methyl aminolevulinate,efaproxiral, porfimer sodium, talaporfin, temoporfin, verteporfin,anagrelide, arsenic trioxide, atrasentan, bortezomib, carmofur,celecoxib, demecolcine, elesclomol, elsamitrucin, etoglucid, lonidamine,lucanthone, masoprocol, mitobronitol, mitoguazone, mitotane, oblimersen,omacetaxine, sitimagene, ceradenovec, tegafur, testolactone,tiazofurine, tipifarnib, and vorinostat.

Examples of retinoid agents include all natural, recombinant, andsynthetic derivatives or mimetics of vitamin A, for example, retinylpalmitate, retinoyl-beta-glucuronide (vitamin A1 beta-glucuronide),retinyl phosphate (vitamin A1 phosphate), retinyl esters, 4-oxoretinol,4-oxoretinaldehyde, 3-dehydroretinol (vitamin A2), 11-cis-retinal(11-cis-retinaldehyde, 11-cis or neo b vitamin A1 aldehyde),5,6-epoxyretinol (5,6-epoxy vitamin A1 alcohol), anhydroretinol (anhydrovitamin A1) and 4-ketoretinol (4-keto-vitamin A1 alcohol), all-transretinoic acid (ATRA; Tretinoin; vitamin A acid;3,7-dimethyl-9-(2,6,6,-trimethyl-1-cyclohenen-1-yl)-2,4,6,8-nonatetraenoicacid [CAS No. 302-79-4]), lipid formulations of all-trans retinoic acid(e.g., ATRA-IV), 9-cis retinoic acid (9-cis-RA; Alitretinoin; Panretin™;LGD1057), 13-cis retinoic acid (Isotretinoin),(E)-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-propenyl]-benzoicacid,3-methyl-(E)-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-propenyl]-benzoicacid, Fenretinide (N-(4-hydroxyphenyl)retinamide; 4-HPR), Etretinate((all-E)-9-(4-methoxy-2,3,6-trimethypheny)-3,7-dimethyl-2,4,6,8-nnatetraenicacid ethyl ester; Tegison), Acitretin((all-E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenicacid; Ro 10-1670; Soriatane; Neotigason), Tazarotene (ethyl6-[2-(4,4-dimethylthiochroman-6-yl)-ethynyl] nicotinate; Tazorac; Avage;Zorac), Tocoretinate (9-cis-tretinoin; Tocoferil), Adapalene(6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid; Differin),Motretinide (trimethylmethoxyphenyl-N-ethyl retinamide; Trasmaderm),retinaldehyde (Retinal), CD437(6-[3-(1-adamantyl)-4-hydroxyphenyl)-2-naphthalene carboxylic acid;AHPN), CD2325, ST1926([E-3-(4′-hydroxy-3′-adamantylbiphenyl-4-yl)acrylic acid), ST1878(methyl2-[3-[2-[3-(2-methoxy-1,1-dimethyl-2-oxoethoxy)phenoxy]ethoxy]phenoxy]isobutyrate),ST2307, ST1898, ST2306, ST2474, MM11453, MM002 (3-CI-AHPC), MX2870-1,MX3350-1, MX84, and MX90-1, docosahexaenoic acid (DHA), phytanic acid(3,7,11,15-tetramethyl hexadecanoic acid), MS6682 (methoprene acid),LG100268 (LG268), LG100324, SR11203([2-(4-carboxyphenyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1,3-dithiane),SR11217(4-(2-methyl-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)propenyl)benzoicacid), SR11234, SR11236(2-(4-carboxyphenyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1,3-dioxane),SR11246, AGN194204, derivatives of 9-cis-RA such as LGD1069 (3-methylTTNEB; Bexarotene; Targretin®;4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl]benzoic acid).

Examples of histone deacetylase inhibitors include, without limitation,MS-275 (SNDX-275; Entinostat), FK228 (FR901228; depsipeptide;Romidepsin), CI-994 (Acetyldinaline; Tacedinaline), Apicidin(cyclo[(2S)-2-amino-8-oxodecanoyl-1-methoxy-L-tryptophyl-L-isoleucyl-(2R)-2-piperidinexcarbonyl]),A-161906 (7-[4-(4-cyanophenyl)phenoxy]-heptanohydroxamic acid),Scriptaid (6-(1,3-Dioxo-1H,3H-benzo[de]isoquinolin-2-yl)-hexanoic acidhydroxyamide), PXD-101 (Belinostat), CHAP (cyclic hydroxamicacid-containing peptide), LAQ-824 (Dacinostat), BML-E1319 (Depudecin),03139 (Oxamflatin), NSC 696085 (Pyroxamide), MW2796; MW2996, T2580(Trapoxin A), AN-9 (Pivanex), W222305 (Tributyrin) Trichostatin A,Trichostatin C, Butyric acid, Valproic acid (VPA), Suberoylanilidehydroxamic acid (SAHA; Vorinostat), m-Carboxycinnamic acidbishydroxamide (CBHA), Salicylbishydroxamic acid (S607; SHA; SHAM);Suberoyl bishydroxamic acid (SBHA); Azelaic bishydroxamic acid (ABHA);Azelaic-1-hydroxamate-9-anilide (AAHA); 3Cl-UCHA(6-(3-chlorophenylureido) caproic hydroxamic acid); and sodium butyrate,4-phenylbutyrate, phenylacetate, valerate, isovalerate, butyramide,isobutyramide, 3-bromopropionate, and valproate.

Also biological drugs, like antibodies, antibody fragments, antibodyconstructs (for example, single-chain constructs), and/or modifiedantibodies (like CDR-grafted antibodies, humanized antibodies, “fullhumanized” antibodies, etc.) directed against cancer or tumormarkers/factors/cytokines involved in cancer can be employed incotherapeutic approaches with the compounds of the invention. Examplesof such biological molecules are alemtuzumab, apolizumab, aselizumab,atlizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumabmertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab,daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab,fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab,labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab,motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab,ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab,pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab,reslivizumab, reslizumab, resyvizumab, rituximab, rovelizumab,rolizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan,tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab,trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab,urtoxazumab, and visilizumab.

Other biologic agents include, but are not limited to, immunomodulatingproteins such as cytokines (such as interleukin-2 (IL-2, Aldesleukin),Epoietin-alpha; EPO), granulocyte-CSF (G-CSF; Filgrastin), andgranulocyte-macrophage-CSF (GM-CSF; Sargramostim) and interferons,(e.g., interferon-alpha, interferon-beta and interferon-gamma), bacillusCalmette-Guerin, levamisole, and octreotide, endostatin, tumorsuppressor genes (e.g., DPC4, NF-1, NF-2, RB, p53, WT1, BRCA1, andBRCA2), and cancer vaccines (e.g., tumor associated antigens such asgangliosides (GM2), prostate specific antigen (PSA), alpha-fetoprotein(AFP), carcinoembryonic antigen (CEA) (produced by colon cancers andother adenocarcinomas, e.g., breast, lung, gastric, and pancreaticcancers), melanoma-associated antigens (MART-I, gap100, MAGE 1,3tyrosinase), papillomavirus E6 and E7 fragments, whole cells orportions/lysates of autologous tumor cells and allogeneic tumor cells.

General Synthetic Route Description

Compounds of Formula I can be synthesized in accordance with or inanalogy to the general routes described below. Unless otherwise stated,in the methods described below the meanings of the differentsubstituents in each synthetic intermediate and in each compound offormula I are the meanings described above with regard to a compound offormula I. Other routes known by the ordinary skilled artisan, as wellas other reactants and intermediates, can also be used to arrive at thecompounds of Formula I. The reaction schemes described below are onlymeant to represent examples of the invention and are in no way meant tobe a limit of the invention. In some of the processes described below itmay be necessary or advisable to protect reactive or labile groups withconventional protecting groups. Both the nature of these protectinggroups and the procedures for their introduction and removal are wellknown in the art (see for example Greene T W and Wuts P G M “Greene'sProtecting Groups in Organic Synthesis”, 4^(th) edition, Wiley, 2006).Whenever a protecting group is present, a subsequent deprotection stepwill be required, which can be performed under standard conditions wellknown in the art, such as those described in the above reference.

In general, the compounds of formula I can be prepared by reductivealkylation of a cyclopropylamino derivative of formula II with a ketoneof formula Ill, as shown below in Scheme 1:

Wherein A, B, D, R^(w), R^(x), R^(y), R^(z) have the meaning disclosedabove in relation to a compound of formula I.

Said reductive alkylation can be performed under standard conditions forreductive alkylations, well known in the art. For example, a suitableset of conditions is reacting II with III using a reducing agent such asa borohydride (e.g., sodium triacetoxyborohydride or sodium borohydride)in a suitable solvent such as dichloroethane or methanol, optionally inthe presence of an acid such as acetic acid. In order to conduct thereaction, it is necessary that any other amino group that may be presenteither in II or in III be protected using conventional amino-protectinggroups to avoid any side reactions; a subsequent deprotection step willbe required then if such amino protecting group is present, in order toobtain a compound of formula I. Any suitable amino-protecting group maybe used, such as for example a tert-butoxycarbonyl (Boc) group. If Bocis used, deprotection can be carried out under standard conditions, forexample under acidic conditions using HCl in an organic solvent such asdiethyl ether or 1,4-dioxane, or trifluoroacetic acid (TFA) indichloromethane. When HCl is used in the last step of the synthesis,compounds of formula I are obtained as a hydrochloride salt. Likewise,if TFA is used, the compounds will be obtained as a trifluoroacetate.

The cyclopropylamino derivatives of formula II and the ketones offormula III are commercially available or can be prepared followingmethods disclosed in the literature.

More detailed methods to obtain compounds of formula I are describedbelow.

The compounds of Formula I wherein R^(w), R^(x), R^(y), R^(z)═H can besynthesized, for example, by the general route described in Scheme 2.This route is particularly suitable for compounds wherein B=H or R¹since the corresponding aldehyde (1) is either commercially available orcan be readily obtained. In Scheme 2 below, for schematic purposes “B”has been omitted.

Aldehydes of Formula (1) are subjected to a Horner-Wadsworth-Emmonsreaction using triethyl phosphono acetate and a base preferablypotassium tert-butoxide in a suitable solvent such as tetrahydrofuran toget the ethyl acrylate derivatives of formula (2) which are thensubjected to cyclopropanation reaction using trimethylsulfoxonium iodideand sodium hydride in dimethyl sulfoxide as a solvent leading to(trans)-ethyl cyclopropanecarboxylate derivatives of formula (3)(obtained as a trans ((1S,2R) and (1R,2S)) racemic mixture). Hydrolysisto the corresponding (trans)-cyclopropanecarboxylic acid derivatives offormula (4) can be performed under basic conditions using for exampleNaOH in a suitable solvent such as MeOH. The subsequent reaction ofcompound (4), first with ethyl chloroformate and triethylamine inacetone and later with sodium azide in water leads to the formation of(trans)-cyclopropanecarbonyl azide derivatives of formula (5). Reactionwith tert-butanol results in the formation of tert-butyl(trans)-cyclopropylcarbamate derivatives of formula (6). Deprotection ofthe Boc-group in acidic conditions, for example using HCl 2M in diethylether in a suitable solvent such as diethyl ether or using HCl in1,4-dioxane, leads to the formation of the (trans)-cyclopropanaminederivatives of formula (7).

Alternatively, the (trans)-cyclopropanamine derivatives of formula (7)can be synthesized by reaction of aldehydes of formula (1) withnitromethane and ammonium acetate using tetrahydrofuran as a solvent,leading to the formation of nitrostyrene of formula (10). Latercyclopropanation reaction using trimetilsulfoxonium iodide and potassiumtert-butoxide results in the formation of trans nitrocyclopropylderivatives of formula (11) (obtained as a trans ((1S,2R), (1R,2S))racemic mixture) and final reduction using zinc in hydrochloric acidaffords the (trans)-cyclopropanamine derivatives of formula (7).

Reductive alkylation of the derivatives of formula (7) with ketones offormula (8) under standard conditions, for example using sodiumtriacetoxyborohydride or sodium borohydride as reducing agent in asuitable solvent such as dichloroethane or methanol leads to theformation of (trans)-cyclopropylamino derivatives of formula (9), whichcorresponds to a compound of formula I, and particularly Ia, whereinR^(w), R^(x), R^(y), R^(z)═H. In case the ketones of formula (8) containa protected amino group, for example a Boc-protected amine(Boc:tert-butoxycarbonyl), an additional deprotection reaction step willbe required to render a compound (9), which can be performed in acidicconditions, for example using HCl 2M in diethyl ether in a suitablesolvent such as diethyl ether, or using HCl in 1,4-dioxane.

Aldehydes of formula (1) and ketones of formula (8) are commerciallyavailable or can be prepared using well known synthetic proceduresstarting from readily available starting materials.

The compounds of Formula I wherein B=-L-E and R^(w), R^(x), R^(y),R^(z)═H and L=—(CH₂)—O— (wherein x is as defined previously) can besynthesized, for example, by the general route described in Scheme 3:

The alkylation of aldehydes of formula 1 (where R¹=—OH) using bromoderivatives of formula (12) (other halo derivatives could also be used)and a base, preferably potassium carbonate in a suitable solvent such asN,N-dimethylformamide leads to the formation of the aldehyde derivativesof formula (13). These are subjected to a Horner-Wadsworth-Emmonsreaction under the same conditions disclosed in Scheme 2 to get theethyl acrylate derivatives of formula (14) which are then subjected tocyclopropanation reaction under the same conditions disclosed in Scheme2 to give the (trans)-ethyl cyclopropanecarboxylate derivatives offormula (15). Following the same conditions disclosed for the conversionof a compound (3) to a compound (7) in scheme 2, a compound (15) isconverted into the (trans)-cyclopropanamine derivative of formula (19).

Alternatively, the (trans)-cyclopropanamine derivatives of formula (19)can be synthesized from aldehydes of formula (13) by conversion into anitrostyrene (21), subsequent cyclopropanation to give a compound (22)and reduction of the nitro group under the same conditions disclosed inscheme 2 for the conversion of a compound (1) into a compound (7) viacompounds (10) and (11).

Reductive alkylation of the derivatives of formula (19) with ketones offormula (8) under the conditions disclosed in scheme 1 or 2 yields acompound (20), which corresponds to a compound of formula I whereinB=-L-E and R^(w), R^(x), R^(y), R^(z)═H and L=—(CH₂)_(x)—O—. In case theketone of formula (8) contains a protected amino group, for example aBoc-protected amine (Boc: tert-butoxycarbonyl), an additionaldeprotection reaction step will be required to render a compound (20),which can be performed in acidic conditions, for example using HCl 2M indiethyl ether in a suitable solvent such as diethyl ether, or using HClin 1,4-dioxane.

Aldehydes of formula (1, where R¹=—OH), bromo derivatives of formula(12) and ketones of formula (8) are commercially available or can beprepared using well known synthetic procedures starting from readilyavailable starting materials.

The compounds of Formula I where B=-L-E and R^(w), R^(x), R^(y), R^(z)═Hand L=—O— can be synthesized, for example, by the general routedescribed in Scheme 4:

Aldehydes of Formula (1, where R¹=Br) are subjected to aHorner-Wadsworth-Emmons reaction under the conditions disclosed inScheme 2 to get the ethyl acrylate derivatives of formula (2, whereR¹=Br) which are then subjected to cyclopropanation reaction under thesame conditions disclosed in Scheme 2 for converting a compound (2) into(3), leading to the (trans)-ethyl cyclopropanecarboxylate derivatives offormula (3, where R¹=Br). Compounds of formula (3) (where R¹=Br) areconverted into the corresponding (trans)-cyclopropanecarboxylic acidderivatives of formula (4, where R¹=Br), which are then converted intothe (trans)-cyclopropanecarbonyl azide derivatives of formula (5, whereR¹=Br) and then into the tert-butyl (trans)-cyclopropylcarbamatederivatives of formula (6, where R¹=Br) following the same conditionsdisclosed in Scheme 2. The reaction of the compounds (6, where R¹=Br)with hydroxy-derivatives of formula (23) using a palladium catalyst suchas Tris(dibenzylideneacetone)dipalladium(0), Xantphos and a base such assodium tert-butoxide in a suitable solvent such as dioxane leads to theformation of tert-butyl (trans)-cyclopropylcarbamate derivatives offormula (24). Deprotection of the Boc-group in acidic conditions, forexample using HCl 2M in diethyl ether in a suitable solvent such asdiethyl ether leads to the formation of the (trans)-cyclopropanaminederivatives of formula (25). Reductive alkylation with ketones offormula (8) under the same conditions disclosed in Scheme 1 or 2 leadsto the formation of (trans)-cyclopropylamino derivatives of formula(26), which correspond to a compound of formula I wherein B=-L-E andR^(w), R^(x), R^(y), R^(z)═H and L is O. In case the ketones of formula(8) contain a protected amino group, for example a Boc-protected amine(Boc: tert-butoxycarbonyl), an additional deprotection reaction stepwill be required to render a compound (26), which can be performed inacidic conditions, for example using HCl 2M in diethyl ether in asuitable solvent such as diethyl ether, or using HCl in 1,4-dioxane.

Aldehydes of formula (1, where R¹=Br), hydroxy-derivatives of formula(25) and ketones of formula (8) are commercially available or can beprepared using well known synthetic procedures starting from readilyavailable starting materials.

The compounds of Formula I wherein B=-L-E and R^(w), R^(x), R^(y),R^(z)═H and L=—NH— or —(CH₂)_(x)—NH— can be synthesized, for example, bythe general route described in Scheme 5.

Tert-butyl (trans)-cyclopropylcarbamate derivatives of formula (6, whereR¹=Br), obtained following the same procedure disclosed in Scheme 4, areconverted into the (trans)-cyclopropanamine derivatives of formula (7,where R¹=Br) by deprotection of the Boc-group in acidic conditions, forexample using HCl 2M in diethyl ether in a suitable solvent such asdiethyl ether or using HCl in 1,4-dioxane. Reductive alkylation ofcompounds (7, R¹=Br) with ketones of formula (8) under the sameconditions disclosed above, for example using sodiumtriacetoxyborohydride or sodium borohydride as reducing agent in asuitable solvent such as dichloroethane or methanol, leads to theformation of (trans)-cyclopropylamino derivatives of formula (9, whereR¹=Br). Reaction of (9, R¹=Br) with di-t-butyl dicarbonate under basicconditions using for example triethylamine in a suitable solvent such astetrahydrofuran leads to the Boc-protected derivatives of formula (27),which are then reacted with amino-derivatives of formula (28) using apalladium catalyst such as Tris(dibenzylideneacetone)dipalladium(0),Xantphos and a base such as sodium tert-butoxide in a suitable solventsuch as dioxane to give the tert-butyl (trans)-cyclopropylcarbamatederivatives of formula (29). Deprotection of the Boc-group of a compound(29) in acidic conditions, for example using HCl 2M in diethyl ether ina suitable solvent such as diethyl ether leads to the formation of the(trans)-cyclopropanamine derivatives of formula (30), which correspondto compound of formula I wherein B=-L-E and R^(w), R^(x), R^(y), R^(z)═Hand L=—NH— or —(CH₂)_(x)—NH—.

Aldehydes of formula (1, where R¹=Br), amines of formula (28) andketones of formula (8) are commercially available or can be preparedusing well known synthetic procedures starting from readily availablestarting materials.

The compounds of Formula I wherein R^(w)=F can be synthesized, forexample, by the general route described in Scheme 6. This method isuseful to obtain compounds having either a trans- or cis-configurationat the cyclopropyl ring (i.e. wherein the B-A- and —NH-D groups are intrans or cis configuration), or mixtures thereof, since thecyclopropanation reaction used yields a mixture of cis/trans isomers, asrepresented by the wavy line in Scheme 6, which can be used as such toobtain compounds of the invention as cis/trans mixtures, or can beseparated if desired to yield at the end of the synthesis the desiredcis or trans products.

Bromofluorination of derivatives of formula (31) usingN-Bromosuccinimide and triethylamine trihydrofluoride in a suitablesolvent such as dichloromethane leads to the formation offluoro-derivatives of formula (32). Elimination reaction using a base,as for example potassium tert-butoxide in a suitable solvent, as forexample pentane leads to fluoro-derivatives of formula (33).Cyclopropanation using ethyl diazoacetate and copper (II)acetylacetonate, as catalyst, in a suitable solvent such asdichloromethane leads to a 1:1 mixtures of cis- and trans-derivatives offormula (34). The diastereomers can be separated at this point eitherchromatographically or, after saponification (performed under basicconditions using for example NaOH in a suitable solvent such as MeOH),by recrystallisation of the corresponding carboxylic acids of formula(35). Curtius degradation to Boc-protected cyclopropylamines of formula(36) can be performed by using a base, as for example, triethylamine,diphenylphosphoryl azide and di-tert-butyl dicarbonate in a suitablesolvent, as for example, tert-butanol. Deprotection of the Boc-group inacidic conditions, for example using HCl 2M in diethyl ether in asuitable solvent such as diethyl ether or HCl in 1,4-dioxane, leads tothe formation of the cyclopropanamine derivatives of formula (37).Reductive alkylation with ketones of formula (8) under the sameconditions disclosed in Scheme 1 or 2 leads to the formation ofcyclopropylamino derivatives of formula (38), which correspond to acompound of formula I wherein R^(w)=F. In case the ketones of formula(8) contain a protected amino group, for example a Boc-protected amine(Boc: tert-butoxycarbonyl), an additional deprotection reaction stepwill be required to render a compound (38), which can be performed inacidic conditions, for example using HCl 2M in a suitable solvent suchas diethyl ether or using HCl in 1,4-dioxane.

Compounds of formula (31) and ketones of formula (8) are commerciallyavailable or can be prepared using well known synthetic proceduresstarting from readily available starting materials.

Compounds of Formula I wherein R^(w) is H, fluoro or C₁₋₄ alkyl andR^(x), R^(y), R^(z)═H can be synthesized, for example, by the generalroute described in Scheme 7 below. This method is useful to obtaincompounds wherein R^(w) is different from hydrogen having either atrans- or cis-configuration at the cyclopropyl ring (i.e. wherein theB-A- and —NH-D groups are in trans or cis configuration), as well ascompounds of formula I wherein R^(w), R^(x), R^(y), R^(z)═H (i.e. acompound of formula Ia) having a cis configuration, since thecyclopropanation reaction used yields a mixture of cis/trans isomers, asrepresented by the wavy line in Scheme 7, which can be separated toyield the desired cis or trans compounds of the invention.

Derivatives of formula (39) are subjected to cyclopropanation usingethyl diazoacetate and copper (I) chloride, as catalyst, in a suitablesolvent such as chloroform, affording a 1:1 mixture of cis- andtrans-derivatives of formula (40). Alternatively, the copper catalystdisclosed in Scheme 6 can be used. The diastereomers can be separated atthis point either chromatographically or, after saponification(performed under basic conditions using for example NaOH in a suitablesolvent such as MeOH), by recrystallisation of the correspondingcarboxylic acids of formula (41). Curtius degradation to Boc-protectedcyclopropylamines of formula (43) can be performed, first by using ethylchloro formate and a base, as for example, triethylamine in a suitablesolvent, as for example, acetone, and subsequent reaction with sodiumazide in water leading to cyclopropanecarbonyl azide derivatives offormula (42). Reaction with tert-butanol results in the formation ofBoc-protected cyclopropylamines of formula (43).

Deprotection of the Boc-group in acidic conditions, for example usingHCl in 1,4-dioxane in a suitable solvent such as 1,4-dioxane or HCl inEt₂O using Et₂O as solvent leads to the formation of thecyclopropanamine derivatives of formula (44). Reductive alkylation withketones of formula (8) under the same conditions disclosed in Scheme 1leads to the formation of cyclopropylamino derivatives of the invention,designated as compounds of formula (45) in the above scheme. In case theketone of formula (8) contains a protected amino group, for example aBoc-protected amine (Boc: tert-butoxycarbonyl), an additionaldeprotection reaction step will be required to render a compound (45),which can be performed in acidic conditions, for example using HCl in1,4-dioxane in a suitable solvent such as 1,4-dioxane or HCl in Et₂Ousing Et₂O as solvent.

Compounds of formula (39) and ketones of formula (8) are commerciallyavailable or can be prepared using well known synthetic proceduresstarting from readily available starting materials.

The compounds of Formula I wherein B=-L-E and R^(w), R^(x), R^(y),R^(z)═H and L=bond can be synthesized, for example, by the general routedescribed in Scheme 8.

Tert-butyl (trans)-cyclopropylcarbamate derivatives of formula (6),obtained by following the same procedure as disclosed in Scheme 4, areconverted into the (trans)-cyclopropanamine derivatives of formula (47)by reaction with boronic acid or ester derivatives of formula (46) usinga suitable solvent such as acetonitrile and water, a base, such as forexample potassium carbonate, and a palladium catalyst such astetrakis(triphenylphospine)palladium (0). Deprotection of the Boc-groupin acidic conditions, for example using HCl in 1,4-dioxane in a suitablesolvent such as 1,4-dioxane leads to the formation of the(trans)-cyclopropanamine derivatives of formula (48). Reductivealkylation with ketones of formula (8) under the same conditionsdisclosed in Scheme 1 leads to the formation of (trans)-cyclopropylaminoderivatives of formula (49), which correspond to compounds of formula Iwherein B=-L-E and R^(w), R^(x), R^(y), R^(z)═H and L=bond. When theketones of formula (8) contain a protected amino group, for example aBoc-protected amine (Boc: tert-butoxycarbonyl), an additionaldeprotection reaction step will be required to render a compound (49).The deprotection can be performed in acidic conditions, for exampleusing HCl 1,4-dioxane in a suitable solvent such as 1,4-dioxane or HClin Et₂O using Et₂O as solvent.

Alternatively, (trans)-cyclopropylamino derivatives of formula (49) canbe synthesized by removal of the Boc-group of tert-butyl(trans)-cyclopropylcarbamate derivatives of formula (6) in acidicconditions, for example using HCl in a suitable solvent such as1,4-dioxane, resulting in the (trans)-cyclopropanamine derivatives offormula (7). Reductive alkylation of compounds (7) with ketones offormula (8) under the same conditions as disclosed in Scheme 1 or 2, forexample using sodium triacetoxyborohydride or sodium borohydride asreducing agent in a suitable solvent such as dichloroethane or methanol,leads to the formation of (trans)-cyclopropylamino derivatives offormula (9). Reaction of (9) with di-t-butyl dicarbonate under basicconditions using for example triethylamine in a suitable solvent suchtetrahydrofuran leads to the Boc-protected derivatives of formula (27).These are converted into the (trans)-cyclopropanamine derivatives offormula (50) by reaction with commercially available boronic acid orester derivatives of formula (46) using a suitable solvent such asacetonitrile and water, a base, such as for example potassium carbonateand a palladium catalyst such as Tetrakis(triphenylphospine) Palladium(0). Removal of the Boc-group in acidic conditions, for example usingHCl in 1,4-dioxane in a suitable solvent such as 1,4-dioxane or HCl inEt₂O using Et₂O as solvent, leads to the formation of the(trans)-cyclopropanamine derivatives of formula (49).

Aldehydes of formula (1), boronic acid or ester derivatives of formula(46) and ketones of formula (8) are commercially available or can beprepared using well known synthetic procedures starting from readilyavailable starting materials.

Furthermore, some compounds of the invention can be obtained from othercompounds of formula I by appropriate interconversion reactions offunctional groups present in a compound of formula I in one or severalsteps, using well known reactions in organic synthesis under standardexperimental conditions. Said transformations can be carried out uponR¹, R² or R³ and include, for example, the substitution of a primary orsecondary amine or of an alcohol by treatment with an alkylating agent,the reduction of a nitro group to an amine, the conversion of an amineinto an amide, sulfonamide, sulfamide, carbamate or urea, thepalladium-catalyzed cross-coupling of amines with aryl halides, etc.Such interconversion reactions can be performed upon a compound offormula I as well as upon any suitable synthetic intermediate describedin the above Schemes.

The salts of a compound of formula I can be obtained during the finalisolation and purification of the compounds of the invention or can beprepared by treating a compound of formula I with a sufficient amount ofthe desired acid (or base) to give the salt in a conventional manner.

In the above schemes 2 to 5 and 8 the cyclopropanation reaction underthe conditions disclosed always leads to a racemic mixture of thetrans-isomers of compounds (3), (11), (15) and (22). If the syntheticprocedures are continued using the trans racemic mixture thus obtained,the corresponding compounds of formula I are obtained as mixtures oftrans-isomers. Likewise, in schemes 6 and 7 the cyclopropanationreaction under the conditions disclosed leads to a mixture of cis/transisomers of compounds (34) and (40). If the synthetic procedure iscontinued using said isomer mixture, the corresponding compounds offormula I are obtained as mixtures of cis/trans isomers. As used herein,cis and trans refers to the disposition of groups -A-B versus —NH-D onthe cyclopropyl ring.

Where the processes for the preparation of the compounds of theinvention give rise to mixtures of stereoisomers, individualstereoisomers of a compound of formula I can be obtained by separationfrom a compound of formula I obtained as a mixture of stereoisomers,using well known methods such as formation of diastereomeric pairs bysalt formation with an optically active acid followed by fractionalcrystallization and regeneration of the free base, or by chiralpreparative chromatography. Alternatively, it is possible to obtainoptically pure or enantiomerically enriched synthetic intermediates,which can then be used as such in subsequent steps, at various stages ofthe synthetic procedures described above, using any known method forchiral resolution. Preferably, the chiral separation is performed upontrans-cyclopropylamines of formula (7), (19), (25), (37) or (48).Separation can also be performed at other stages of the procedure, forexample upon a compound of formula (34) or (40). A suitable method toobtain the enantiomers of the trans cyclopropylamines (7), (19), (25),(37) and (48) comprises contacting a trans-substituted cyclopropylaminewith a chiral recrystallization agent in a solvent (particularly underconditions that are sufficient for the crystallization of the salt ofthe chiral recrystallization agent and the trans substitutedcyclopropylamine); and isolating the crystallized salt of the chiralrecrystallization agent and the trans substituted cyclopropylamine,thereby preparing an enantiomer of a trans N-substitutedcyclopropylamine. A suitable chiral recrystallization agent is S (+)mandelic acid, D (−) tartaric acid, L (+) tartaric acid, L (−)di-p-toluoyl tartaric acid, or R (−) mandelic acid. Suitable solventsare tetrahydrofuran, ethanol or mixtures thereof with H₂O.

Alternatively, it is possible for a person skilled in the art to obtainoptically pure or enantiomerically enriched final compounds (orsynthetic intermediates) by using chiral chromatography.

EXAMPLES

Unless stated otherwise, in the compounds of all Examples of the presentspecification the stereochemical configuration is defined by thechemical name indicated for the respective compound, even though thedrawn structure may represent a more specific configuration.Nevertheless, the invention relates to all stereoisomers of thecompounds described and defined herein. Accordingly, the inventionencompasses the compounds described in the Examples as defined by theirchemical names and, in addition thereto, also the correspondingcompounds having the absolute configuration shown in the respectivedrawn structures.

The following abbreviations have been used:

ACN: acetonitrile, AcOH: acetic acid, aq: aqueous, Boc:tert-butyloxycarbonyl, (Boc)₂O: di-tert-butyl dicarbonate, brm: broadmultiplet, brs: broad singlet, Cu(acac)₂: copper(II) acetylacetonate, d:doublet, DCE: 1,2-dichloroethane, DCM: dichloromethane, DMF:N,N-dimethylformamide, DMSO: dimethylsulfoxide, DPPA: diphenylphosphorylazide, Et₂O: diethyl ether, EtOAc: ethyl acetate, HPLC: high performanceliquid chromatography, m: multiplet, MEM: methoxy methyl ether, MeOH:methanol, NBS: N-bromosuccinimide, NMR: nuclear magnetic resonance,Pd₂(dba)₃: tris(dibenzylideneacetone)dipalladium(0), Pet ether:petroleum ether, q: quadruplet, Rf: retention factor, RT: roomtemperature, s: singlet, sat.: saturated, t: triplet, TEA:triethylamine, THF: tetrahydrofuran, TLC: thin layer chromatography,Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene.

Intermediate A: 1-(benzyloxy)-4-[(trans)-2-nitrocyclopropyl]benzene

Trimethylsulfoxonium iodide (0.62 g, 2.82 mmol) was added in portions toa solution of t-BuOK (0.32 g, 2.82 mmol) in dry DMSO (5 mL). After 10min a solution of 1-(benzyloxy)-4-[(E)-2-nitrovinyl]benzene (0.60 g,2.35 mmol) in DMSO (5 mL) was transferred via canula and the mixture wasstirred at room temperature for 6 h. The reaction was poured over water(10 mL) and extracted with Et₂O (3×10 mL); the organic layers werewashed with brine (2×15 mL), dried over anhydrous Na₂SO₄ and filtered.After removal of the solvent, the residual orange oil was purified bycolumn chromatography on silica gel (5% EtOAc/hexanes) affording 0.16 gof 1-(benzyloxy)-4-[(trans)-2-nitrocyclopropyl]benzene [Rf=0.5 (20%EtOAc/hexanes), white solid, 26% yield].

Intermediate B: Trans-2-[4-(benzyloxy)phenyl]cyclopropanamine

Zn dust (1.97 g, 30 mmol) was added in small portions, over a period of30 min, to a vigorously stirred solution of1-(benzyloxy)-4-[(trans)-2-nitrocyclopropyl]benzene (Intermediate A,0.81 g, 3.0 mmol) in i-PrOH (25 mL) and HCl (11 mL of aqueous solution2.7 N, 30 mmol). After 17 h the mixture was filtered through a pad ofcelite, that was washed with 10 mL of methanol. The filtrate wasconcentrated and 10 mL of water were added, washing with CH₂Cl₂ (3×15mL). The organic layers were dried over anhydrous Na₂SO₄ and filtered.After removal of the solvent, the crude product was purified by columnchromatography on silica gel (10% MeOH/CH₂Cl₂) affording 0.50 g of(trans)-2-[4-(benzyloxy)phenyl]cyclopropanamine [Rf=0.2 (10%MeOH/CH₂Cl₂), white solid, 70% yield].

¹H-NMR (MeOH, 250 MHz, δ): 7.45-7.27 (m, 5H, ArH); 6.96 (d, J=8.5 Hz,2H, ArH); 6.86 (d, J=8.5 Hz, 2H, ArH); 5.03 (s, 2H, CH2); 2.41-2.34 (m,1H, CH); 1.86-1.76 (m, 1H, CH); 0.98-0.85 (m, 2H, CH2).

Intermediate C: 4-(benzyloxy)benzaldehyde

Potassium Carbonate (678 g, 4.91 mol) was added to a solution of4-hydroxybenzaldehyde (200 g, 1.63 mol) in DMF (2 L) followed to theaddition of benzyl bromide (214 mL, 1.80 mol) at 0° C. and stirred for18 h at RT. After completion, the reaction mixture was poured into icewater (3 L), filtered the solid and dried to get4-(benzyloxy)benzaldehyde (230 g, 66%).

Intermediate D: (E)-ethyl 3-(4-(benzyloxy)phenyl)acrylate

Triethyl phosphonoacetate (259 mL, 1.3 mol) was added slowly dropwise toa solution of Potassium-tert-butoxide (145 g, 1.29 mol) in dry THF (2 L)at −5° C. and stirred for 30-45 mins. Then a solution of4-(benzyloxy)benzaldehyde (Intermediate C, 230 g, 1.08 mol) in dry THF(1.5 L) was added slowly dropwise at −10° C. over a period of 15 minsand stirred for 30 mins. After completion, the reaction mixture waspoured into ice water (1 L) and extracted with EtOAc (2×1.5 L). Thecombined organic extracts were washed with sat NaHCO₃ solution (1 L),water (1 L), brine (1 L), dried over anhydrous Na₂SO₄, filtered andevaporated to get crude (E)-ethyl 3-(4-(benzyloxy)phenyl)acrylate (290g, 95%). The crude was carried to next step without furtherpurification.

Intermediate E: (Trans)-ethyl2-(4-(benzyloxy)phenyl)cyclopropanecarboxylate

Trimethyl sulfoxonium iodide (224 g, 1.02 mol) was added portion wise toa suspension of NaH (40.8 g, 1.02 mol) in dry DMSO (2 L) at RT over aperiod of 20 min and stirred for 1 h till the formation of a clearsolution. A solution of (E)-ethyl 3-(4-(benzyloxy) phenyl) acrylate(Intermediate D, 240 g, 0.85 mol) in dry DMSO (2 L) was added dropwiseand stirred at RT for 30 mins. After completion, the reaction mixturewas poured into ice water (2 L), extracted with EtOAc (2×1 L). Combinedorganic extracts were washed with ice water (1 L), brine (1 L), driedover anhydrous Na₂SO₄, filtered and evaporated to afford (Trans)-ethyl2-(4-(benzyloxy)phenyl)cyclopropanecarboxylate (142 g, 58.6%) as an offwhite solid. The crude was carried to next step without furtherpurification.

Intermediate F: (Trans)-2-(4-(benzyloxy)phenyl)cyclopropanecarboxylicAcid

4N NaOH solution (4 L) was added to a solution of (trans)-ethyl2-(4-(benzyloxy)phenyl)cyclopropanecarboxylate (Intermediate E, 250 g,0.844 mol) in Methanol (1.2 L) at 0° C. and stirred at RT for 4 h. Aftercompletion, the solvent was evaporated, the residue was diluted withwater (1 L), acidified with 4 N HCl solution, extracted with EtOAc (2×2L). Combined organic extracts were washed with water (1 L), brine (1 L),dried over anhydrous Na₂SO₄, filtered and evaporated to afford(trans)-2-(4-(benzyloxy)phenyl)cyclopropanecarboxylic acid (190 g, 84%)as off white solid. The crude was carried to next step without furtherpurification.

Intermediate G: (Trans)-2-(4-(benzyloxy)phenyl)cyclopropanecarbonylazide

Ethyl chloroformate (143 mL, 1.48 mol) was added to a solution of(trans)-2-(4-(benzyloxy) phenyl) cyclopropanecarboxylic acid(Intermediate F, 190 g, 0.70 mol), Triethyl amine (229 mL, 1.63 mol) inacetone (2.8 L) at −20° C. and stirred for 1 h, then a solution of NaN₃(138 g, 2.1 mol) in water (200 mL) was added and stirred at RT for 30mins. After completion, the solvent was evaporated, residue wasdissolved in EtOAc (2 L), washed with water (2 L), brine (1 L), driedover anhydrous Na₂SO₄, filtered and evaporated to afford(trans)-2-(4-(benzyloxy)phenyl)cyclopropanecarbonyl azide (178 g,85.9%).

Intermediate H: Tert-butyl((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)carbamate

A solution of (trans)-2-(4-(benzyloxy)phenyl)cyclopropanecarbonyl azide(Intermediate G, 178 g, 0.64 mol) in tert-butanol (2.6 L) was heated at90° C. for 16 h. After completion, the solvent was evaporated and thecrude residue was purified by column chromatography by using (SiO₂)EtOAc:Pet ether (4:96) to get tert-butyl((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)carbamate (78 g, 37.8%) asoff-white solid.

Intermediate I: (E)-ethyl 3-(6-bromopyridin-3-yl)acrylate

Triethyl phosphonoacetate (26.6 g, 118.8 mmol) was added slowly dropwiseto a mixture of Potassium-tert-butoxide (14.5 g, 129.6 mmol) in dry THF(200 mL) at −5° C., stirred for 20 min and then a solution of6-bromopyridine-3-carboxaldehyde (20 g, 108 mmol) in dry THF (100 mL)was added slowly dropwise at −5° C. and stirred for 30 min. Aftercompletion, the reaction mixture was poured into ice water (350 mL) andextracted with EtOAc (2×300 mL). The combined organic extracts werewashed with saturated NaHCO₃ solution (250 mL), water (250 mL) and brine(250 mL) and dried over anhydrous Na₂SO₄, filtered and evaporated to get(E)-ethyl 3-(6-bromopyridin-3-yl) acrylate (20 g, 72.9%) as brown colorliquid. This is carried to next step without further purification.

Intermediate J:(Trans)-ethyl-2-(6-bromopyridin-3-yl)cyclopropanecarboxylate

Trimethyl sulfoxonium iodide (20.8 g, 94.7 mmol) was added in smallportions to a suspension of sodium hydride (4 g, 170.6 mmol) in dry DMSO(400 mL) at rt., stirred for 1 h until clear solution was obtained. Asolution of (E)-ethyl 3-(6-bromopyridin-3-yl) acrylate (Intermediate I,20 g, 78.7 mmol) in dry DMSO (20 mL) was added and stirred for 4 h.After completion, the reaction mixture was poured into ice water (700mL), extracted with EtOAc (2×350 mL). The combined organic extracts werewashed with water (250 mL), brine (250 mL) and dried over anhydrousNa₂SO₄, filtered and evaporated to give(trans)-ethyl-2-(6-bromopyridin-3-yl)cyclopropanecarboxylate (10 g, 47%)as brown liquid.

Intermediate K: (Trans)-2-(6-bromopyridin-3-yl)cyclopropanecarboxylicacid hydrochloride

NaOH 4N solution (60 mL) was added to a solution of(trans)-ethyl-2-(6-bromopyridin-3-yl)cyclopropanecarboxylate(Intermediate J, 10 g, 37.1 mmol) in methanol (100 mL) and the reactionmixture was stirred at RT for 4 h. After completion, the solvent wasevaporated and the residue was diluted with ice water (250 mL) andacidified with 4 N HCl solution, the aqueous layer was extracted withEtOAc (2×350 mL). The combined organic extracts were washed with water(250 mL), brine (250 mL) and dried over anhydrous Na₂SO₄, filtered andevaporated to give (trans)-2-(6-bromopyridin-3-yl)cyclopropanecarboxylicacid hydrochloride (5 g, 55.8%) as a light brown color solid.

Intermediate L: (Trans)-2-(6-bromopyridin-3-yl)cyclopropanecarbonylazide

Ethyl chloroformate (5.8 mL, 62 mmol) was added to a solution of(trans)-2-(6-bromopyridin-3-yl)cyclopropanecarboxylic acid hydrochloride(Intermediate K, 5 g, 20.7 mmol) and Et₃N (14.2 mL, 103.7 mmol) inAcetone (100 mL) at −5° C., then reaction mixture was stirred at −5° C.for 1 h, then a solution of NaN₃ (2.7 g, 41.4 mmol) in water (10 mL) wasadded and stirred for 30 mins at RT. After completion the solvent wasevaporated under vacuum. The crude residue was dissolved in ethylacetate (200 mL), washed with water (80 mL), brine (80 mL), dried overanhydrous Na₂SO₄, filtered and evaporated to get(trans)-2-(6-bromopyridin-3-yl)cyclopropanecarbonyl azide (2.5 g, 45.5%)as a brown color gummy liquid.

Intermediate M: tert-butyl(trans)-2-(6-bromopyridin-3-yl)cyclopropylcarbamate

A solution of (trans)-2-(6-bromopyridin-3-yl)cyclopropanecarbonyl azide(Intermediate L, 2.5 g, 9.36 mmol) in tert-butanol (80 mL) was heated at90° C. for 16 h. After completion, the solvent was evaporated undervacuum and the residue was taken in water (100 mL) and extracted withEtOAc (2×100 mL). The combined organic extracts were washed with water(100 mL), brine (100 mL) and dried over anhydrous Na₂SO₄, filtered andevaporated. The crude residue was purified by flash columnchromatography (SiO₂) by eluting with EtOAc:Hexane (2:8) to gettert-butyl (trans)-2-(6-bromopyridin-3-yl)cyclopropylcarbamate (1.1 g,37.5%) as a light yellow solid.

¹H-NMR (CDCl₃) δ (ppm): 1.16 (q, 1H), 1.23 (quin, 1H), 1.45 (s, 9H),2.01 (m, 1H), 2.69 (m, 1H), 4.88 (br, 1H), 7.36 (s, 2H), 8.20 (s, 1H).

Intermediate N: (E)-ethyl 3-(4-bromophenyl)acrylate

A solution of triethyl phosphonoacetate (13.1 g, 0.0589 mol) was addedslowly (dropwise) to a solution of Potassium-tert-butoxide (6.59 g,0.0589 mol), in dry THF (150 mL) at −5° C., stirred for 30-45 mins atthe same temperature, then a solution of 4-Bromo benzaldehyde (10 g,0.054 mol), in dry THF (50 mL) was slowly added dropwise at −5° C. overa period of 15 mins, stirred the reaction mixture for 30 mins at thesame temperature. After completion of reaction by TLC, the reactionmixture was poured into ice water (300 mL), extracted with EtOAc (2×200mL). The combined organic extracts were washed with sat NaHCO₃ solution(200 mL), water (200 mL), brine (200 mL) and dried over anhydrousNa₂SO₄, filtered and evaporated to get crude (E)-ethyl 3-(4-bromophenyl)acrylate (10 g, 72%) as pale green liquid. This is carried to next stepwithout further purification.

Intermediate O: (Trans)-ethyl 2-(4-bromophenyl)cyclopropanecarboxylate

Trimethyl sulfoxonium iodide (5.19 g, 0.0236 mol) was added slowly insmall portions over a period of 20 min. to a suspension of sodiumhydride (0.44 g, 0.0236 mol) in dry DMSO (80 mL) at rt, stirred for 1 h,till the formation of clear solution. Then a solution of (E)-ethyl3-(4-bromophenyl) acrylate (Intermediate N, 5 g, 0.01968), in dry DMSO(20 mL) was added slowly dropwise, stirred at rt for 30 mins. Aftercompletion of reaction, checked by TLC, the reaction mixture was pouredinto ice water (200 mL), extracted with EtOAc (2×150 mL). Combinedorganic extracts were washed with ice water (2×150 mL), brine (150 mL),dried over anhydrous Na₂SO₄, filtered and evaporated to get(trans)-ethyl 2-(4-bromophenyl)cyclopropanecarboxylate (4 g, 75.9%) as agreen liquid. The crude is carried to next step without furtherpurification.

Intermediate P: (Trans)-2-(4-bromophenyl)cyclopropanecarboxylic Acid

NaOH 4N (20 mL) was added to a solution of (trans)-ethyl2-(4-bromophenyl)cyclopropanecarboxylate (Intermediate O, 4 g, 0.0149mol), in Methanol (40 mL) and stirred at rt for 2 h. After completion ofreaction, checked by TLC, the solvent was evaporated and the residue wasdiluted with water (50 mL), acidified with HCl 4 N solution, the solidformed was filtered and dried to get(trans)-2-(4-bromophenyl)cyclopropanecarboxylic acid (2.59 g, 72%), as awhite solid.

Intermediate Q: (Trans)-2-(4-bromophenyl)cyclopropanecarbonyl azide

Ethyl chloroformate (1.9 mL) was added to a solution of(trans)-2-(4-bromophenyl) cyclopropanecarboxylic acid (Intermediate P, 4g, 0.0165 mol) and Et₃N (2.51 mL, 0.0199 mol) in acetone (60 mL) at −20°C., stirred at same temperature for 1 h, then a solution of NaN₃ (1.3 g,0.0199 mol) in water (5 mL), was added and stirred for 30 mins at rt.After completion of reaction, checked by TLC, the solvent was evaporatedand crude residue was dissolved in ethyl acetate (100 mL), washed withwater (40 mL), dried over anhydrous Na₂SO₄, filtered and evaporated toget (trans)-2-(4-bromophenyl)cyclopropanecarbonyl azide (4 g). The cruderesidue is carried to next step without further purification.

Intermediate R: tert-butyl (trans)-2-(4-bromophenyl)cyclopropylcarbamate

A solution of (trans)-2-(4-bromophenyl) cyclopropanecarbonyl azide(Intermediate Q, 4 g) in tert-Butanol (40 mL) was heated at 90° C. for16 h. After completion of reaction, checked by TLC, the solvent wasevaporated residue was poured into water (50 mL), extracted with EtOAc(2×50 mL). The combined organic extracts were washed with water (50 mL),brine (50 mL), dried over anhydrous Na₂SO₄, filtered and evaporated. Thecrude residue was purified by column chromatography (SiO₂) by elutingwith EtOAc:Petroleum ether (2:98), to get tert-butyl(trans)-2-(4-bromophenyl)cyclopropylcarbamate (2.5 g, 48% overall 2steps) as a white solid.

¹H-NMR (CDCl₃, 250 MHz) δ: 1.07-1.19 (m, 2H), 1.44 (s, 9H); 2.05-1.94(m, 1H); 2.72-2.62 (m, 1H); 4.85 (br, 1H,); 7.09-6.96 (m, 2H); 7.44-7.33(m, 2H).

Intermediate S: (E)-ethyl 3-(pyridin-3-yl)acrylate

A solution of triethyl phosphonoacetate (66.75 mL, 336.44 mmol) wasadded dropwise to a solution of Potassium-tert-butoxide (37.7 g, 280.37mmol) in dry THF (300 mL) at −5° C. over a period of 10 mins and stirredat 0° C. for 30 mins. Then a solution of nicotinaldehyde (30 g, 280.37mmol) in dry THF (50 mL) was added dropwise at 0° C. over a period of 15mins and stirred at RT for 2 h. After completion, the reaction mixturewas poured into ice water (150 ml) and extracted with EtOAc (2×300 mL).The combined extracts were washed with sat NaHCO₃ solution (200 mL),water (200 mL), brine (200 mL), dried over anhydrous Na₂SO₄, filteredand evaporated to afford crude liquid (E)-ethyl 3-(pyridin-3-yl)acrylate (42 g, 84.67%). The crude was carried to next step withoutfurther purification.

Intermediate T: (Trans)-ethyl 2-(pyridin-3-yl)cyclopropanecarboxylate

Trimethyl sulfoxonium iodide (14.90 g, 67.76 mmol) was added portionwise to a suspension of NaH (2.71 g, 67.76 mmol) in dry DMSO (100 mL) atRT over a period of 20 min. and stirred for 1 h till the formation of aclear solution. A solution of (E)-ethyl 3-(pyridin-3-yl) acrylate(Intermediate S, 10 g, 56.47 mmol) in dry DMSO (50 mL) was addeddropwise and stirred at RT for 20 min. After completion, the reactionmixture was poured into ice water (200 mL), extracted with EtOAc (2×200mL). Combined organic extracts were washed with ice water (150 mL),brine (150 mL), dried over anhydrous Na₂SO₄, filtered and evaporated toafford (trans)-ethyl 2-(pyridin-3-yl)cyclopropanecarboxylate (4 g,37.07%) as pale brown liquid. The crude was carried to next step withoutfurther purification.

Intermediate U: (Trans)-2-(pyridin-3-yl)cyclopropanecarboxylic Acid

A solution of NaOH (7.116 g in 45 mL of H₂O, 177.92 mmol) was added to asolution of (trans)-ethyl 2-(pyridin-3-yl) cyclopropanecarboxylate(Intermediate T, 17 g, 88.96 mmol) in Methanol (170 mL) at 0° C. andstirred at RT for 16 h. After completion, the solvent was evaporated,the residue was diluted with water (50 mL), neutralized with Acetic acidand extracted with EtOAc (4×100 mL). The combined extracts were washedwith water (100 mL), brine (100 mL), dried over anhydrous Na₂SO₄,filtered and evaporated to afford(trans)-2-(pyridin-3-yl)cyclopropanecarboxylic acid (9 g, 62.06%) as offwhite solid. The crude was carried to next step without furtherpurification.

Intermediate V: (Trans)-2-(pyridin-3-yl)cyclopropanecarbonyl azide

Ethyl chloroformate (6.89 mL, 71.15 mmol) was added to a solution of(trans)-2-(pyridin-3-yl)cyclopropanecarboxylic acid (Intermediate U, 9g, 55.194 mmol) and triethyl amine (11.03 mL, 82.79 mmol) in acetone (90mL) at −20° C. and stirred for 1 h, then a solution of NaN₃ (5.38 g,82.79 mmol) in water (25 mL) was added and stirred at RT for 30 mins.After completion, the solvent was evaporated, residue was dissolved inEtOAc (100 mL), washed with water (2×50 mL), brine (50 mL), dried overanhydrous Na₂SO₄, filtered and evaporated to afford(trans)-2-(pyridin-3-yl)cyclopropanecarbonyl azide (8.4 g, 81%). Thecrude was carried to next step without further purification.

Intermediate W: tert-butyl((trans)-2-(pyridin-3-yl)cyclopropyl)carbamate

A solution of (trans)-2-(pyridin-3-yl)cyclopropanecarbonyl azide(Intermediate V, 8.4 g, 44.66 mmol) in tert-butanol (85 mL) was heatedat 90° C. for 16 h. After completion, the solvent was evaporated andcrude residue was purified by column chromatography (SiO₂) usingEtOAc:Petroleum ether (25:75) to afford tert-butyl(trans)-2-(pyridin-3-yl) cyclopropylcarbamate (3.9 g, 37.32%) ascolourless liquid.

Intermediate X: (Trans)-2-(pyridin-3-yl)cyclopropanamine hydrochloride

HCl in Dioxane (10 mL) was added to a solution of tert-butyl(trans)-2-(pyridin-3-yl)cyclopropylcarbamate (Intermediate W, 2 g, 8.541mmol) in 1,4-dioxane (10 mL) at 0° C. and stirred at RT for 12 h. Aftercompletion, the solvent was evaporated and the residue was trituratedwith diethyl ether (20 mL) followed by hexane (20 mL) to get(trans)-2-(pyridin-3-yl)cyclopropanamine hydrochloride (1.2 g, 82.7%).

Intermediate Y: (E)-ethyl 3-(thiazol-5-yl)acrylate

A solution of triethyl phosphonoacetate (11.88 g, 53.03 mmol) was addeddropwise to a solution of Potassium-tert-butoxide (5.94 g, 53.03 mmol)in dry THF (100 mL) at −5° C. and stirred for 30 mins. A solution ofthiazole-5-carbaldehyde (5 g, 44.19 mmol) in dry THF (25 mL) was thenadded dropwise at −5° C. over a period of 15 mins and stirred for 30mins. After completion, the reaction mixture was poured into ice water(150 mL), extracted with EtOAc (2×100 mL). The combined extracts werewashed with sat NaHCO₃ solution (100 mL), water (100 mL), brine (100mL), dried over anhydrous Na₂SO₄, filtered and evaporated to affordcrude (E)-ethyl 3-(thiazol-5-yl)acrylate (10 g, 82.3%) as a white solid.The crude was carried to next step without further purification.

Intermediate Z: (Trans)-ethyl 2-(thiazol-5-yl)cyclopropanecarboxylate

Trimethyl sulfoxonium iodide (14.40 g, 65.49 mmol) was added portionwiseto a suspension of NaH (2.61 g, 108.75 mmol) in dry DMSO (200 mL) at RTover a period of 20 min and stirred for 1 h till the formation of clearsolution. A solution of (E)-ethyl 3-(thiazol-5-yl)acrylate (IntermediateY, 10 g, 54.57 mmol) in dry DMSO (50 mL) was then added dropwise andstirred at RT for 30 mins. After completion, the reaction mixture waspoured into ice water (100 mL) and extracted with EtOAc (2×100 mL).Combined organic extracts were washed with water (2×50 mL), brine (50mL), dried over anhydrous Na₂SO₄, filtered and evaporated to affordtrans-ethyl 2-(thiazol-5-yl)cyclopropanecarboxylate (8 g, 61.9%) as areddish brown liquid. The crude was carried to next step without furtherpurification.

Intermediate AA: (Trans)-2-(thiazol-5-yl)cyclopropanecarboxylic Acid

A 4N NaOH solution (40 mL) was added to a solution of trans-ethyl2-(thiazol-5-yl)cyclopropanecarboxylate (Intermediate Z, 8 g, 40.55mmol) in methanol (80 mL) and stirred at RT for 4 h. After completion,the solvent was evaporated, the residue was diluted with water (50 mL),acidified with Acetic acid and extracted with EtOAc (2×75 mL). Thecombined extracts were washed with water (50 mL), brine (50 mL), driedover anhydrous Na₂SO₄, filtered and evaporated to affordtrans-2-(thiazol-5-yl)cyclopropanecarboxylic acid (4 g, 58.30%). Thecrude was carried to next step without further purification.

Intermediate AB: (Trans)-2-(thiazol-5-yl)cyclopropanecarbonyl azide

Ethyl chloroformate (3.34 g, 30.76 mmol) was added to a solution oftrans-2-(thiazol-5-yl)cyclopropanecarboxylic acid (Intermediate AA, 4 g,26.3 mmol) and triethylamine (3.62 g, 35.50 mmol) in acetone (40 mL) at−20° C., stirred at same temperature for 1 h. A solution of NaN₃ (2.84g, 47.33 mmol) in water (10 mL) was then added and stirred at RT for 30mins. After completion, the solvent was evaporated, the crude residuewas dissolved in EtOAc (100 mL), washed with water (50 mL), brine (50mL), dried over anhydrous Na₂SO₄, filtered and evaporated to affordtrans-2-(thiazol-5-yl)cyclopropanecarbonyl azide (3 g, 58.7%) as brownliquid. The crude was carried to next step without further purification.

Intermediate AC: tert-butyl((trans)-2-(thiazol-5-yl)cyclopropyl)carbamate

A solution of trans-2-(thiazol-5-yl)cyclopropanecarbonyl azide(Intermediate AB, 3 g, 15.44 mmol) in tert-butanol (60 mL) was heated at90° C. for 16 h. After completion, the solvent was evaporated and theresidue was taken in water (50 mL), extracted with EtOAc (2×50 mL). Thecombined organic extracts were washed with water (50 mL), brine (50 mL),dried over anhydrous Na₂SO₄, filtered and evaporated. The crude residuewas purified by column chromatography (SiO₂) by using EtOAc:Petroleumether (20:80) to get tert-butyltrans-2-(thiazol-5-yl)cyclopropylcarbamate (1.1 g, 29.64%) as a paleyellow liquid.

Intermediate AD: (Trans)-2-(thiazol-5-yl)cyclopropanamine hydrochloride

HCl in dioxane (10 mL) was added to a solution of tert-butyltrans-2-(thiazol-5-yl)cyclopropylcarbamate (Intermediate AC, 1.1 g,45.83 mmol) in dioxane (10 mL) at 15° C. and stirred at RT for 3 h.After completion, the solvent was evaporated, the residue was trituratedwith EtOAc to afford trans-2-(thiazol-5-yl)cyclopropanaminehydrochloride (600 mg, 74.8%) as pale yellow solid.

Intermediate AE: tert-butyl((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)carbamate

A solution of tert-butyl(trans)-2-(6-bromopyridin-3-yl)cyclopropylcarbamate (Intermediate M, 100mg, 0.32 mmol), potassium carbonate (132 mg, 0.96 mmol) and3-trifluoromethylbenzeneboronic acid (72 mg, 0.38 mmol) in CH₃CN:H₂O(4:1) (10 mL) was degassed for 30 mins. Tetrakis triphenylphosphinepalladium (37 mg, 0.032 mmol) was added and degassed for 10 mins and thereaction mixture was heated at reflux temperature for 2 h. Aftercompletion, the reaction mixture was poured in ice water (100 mL),extracted with ethyl acetate (5×40 mL). The combined extract was washedwith water (70 mL), brine (70 mL), dried over anhydrous Na₂SO₄, filteredand evaporated. The crude residue was purified by column chromatography(SiO₂), by using EtOAc:Petroleum ether (1:9) to get tert-butyl(trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylcarbamate(70 mg, 58.3%) as a white solid.

¹H-NMR (CDCl₃) δ (ppm): 1.26 (m, 2H), 1.46 (s, 9H), 2.10 (m, 1H), 2.78(m, 1H), 4.86 (br, 1H), 7.55 (m, 2H), 7.65 (t, 2H), 8.14 (d, 1H), 8.24(s, 1H), 8.54 (s, 1H). MS (M+H): 379.1.

Intermediate AF:(Trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanaminedihydrochloride

HCl in diethyl ether (5 mL) was added to a solution of tert-butyl(trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylcarbamate(Intermediate AE, 70 mg, 0.185 mmol) in diethyl ether (10 mL) at 0° C.slowly dropwise over a period of 10 mins and then stirred for 2 h. Aftercompletion, the reaction mixture was filtered under inert atmosphere andwashed with hexane (10 mL), EtOAC (5 mL), and dried under reducedpressure to get(trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropanaminedihydrochloride (50 mg, 86.2%) as a pale yellow powder.

¹H-NMR (D₂O) δ (ppm): 1.52 (q, 1H), 1.63 (quin, 1H), 2.66 (m, 1H), 3.08(m, 1H), 7.72 (t, 1H), 7.89 (d, 1H), 7.98 (d, 1H), 8.09 (s, 1H), 8.14(d, 1H), 8.27 (d, 1H), 8.61 (s, 1H). MS (M+H): 279.1.

Intermediate AG: tert-butyl((trans)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)carbamate

A solution of tert-butyl (trans)-2-(4-bromophenyl)cyclopropylcarbamate(Intermediate R, 1 g, 3.2 mmol), potassium carbonate (1.31 g, 9.6 mmol)and 3-(trifluoromethyl) phenylboronic acid (0.73 g, 3.8 mmol) inacetonitrile:water (4:1) was degassed for 30 mins. Tetrakistriphenylphosphine palladium (36 mg, 0.032 mmol) was then added,degassed again for 10 mins and the reaction mixture was heated at refluxtemperature for 5 h. After completion, the reaction mixture was pouredin ice water (50 mL) and extracted with ethyl acetate (2×50 mL).Combined extracts were washed with water (70 mL), brine (70 mL), driedover anhydrous Na₂SO₄ and then filtered and evaporated. The cruderesidue was purified by column chromatography (SiO₂), by usingEtOAc:Petroleum ether (2:8) to get tert-butyl((trans)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)carbamate(0.8 g, 66%) as a white solid.

Intermediate AH:(Trans)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropanaminehydrochloride

HCl in diethyl ether (3 mL) was added slowly dropwise to a solution oftert-butyl((trans)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)carbamate(Intermediate AG, 200 mg, 0.53 mmol) in diethyl ether (5 mL) at 10° C.over a period of 10 min and then stirred for 4 h. After completion, thesolvent was evaporated and the residue was triturated with hexane (5mL), diethyl ether (5 mL) and dried under reduced pressure to get(trans)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropanaminehydrochloride (140 mg, 77.8%) as a white solid.

¹H-NMR (DMSO-d6) δ (ppm): 1.27 (q, 1H), 1.46 (quin, 1H), 2.41 (m, 1H),2.86 (m, 1H), 7.29 (d, 2H), 7.69 (m, 4H), 7.96 (m, 2H), 8.53 (s, 1H),8.61 (br, 2H). MS (M+H): 278.3

Intermediate AI: 4,4-dimethoxycyclohexanecarboxamide

HCl in methanol (2 mL) was added to a solution of ethyl4-oxocyclohexanecarboxylate (5 g, 29.41 mmol) in methanol (2 mL) at RT,stirred at RT for 3 h and then aq. ammonia (30 mL) was added and heatedat 90° C. in a sealed tube for 48 h. After completion, solvent wasevaporated. The crude was purified by column chromatography (SiO₂) toafford 4,4-dimethoxycyclohexanecarboxamide (1.2 g, 31.8%) as whitesolid.

Intermediate AJ: 4-oxocyclohexanecarboxamide

p-toluene sulphonic acid (500 mg, 2.90 mmol) was added to a solution of4,4-dimethoxycyclohexanecarboxamide (Intermediate AI, 1.2 g, 7.36 mmol)in acetone-water (1:1) (20 mL) and heated to 60° C. for 3 h. Aftercompletion, the reaction mixture was poured into ice water (20 mL),extracted with 40% isopropanol in chloroform (3×30 mL). The combinedextracts were washed with water, brine, dried over anhydrous Na₂SO₄,filtered and evaporated. The crude product was washed with 10%dichloromethane in petroleum ether to afford 4-oxocyclohexanecarboxamide(410 mg, 45.55%) as white solid.

Intermediate AK: 4-aminocyclohexanone hydrochloride

HCl in dioxane (1 mL) was added dropwise to a solution of tert-butyl4-oxocyclohexylcarbamate (200 mg, 0.938 mmol) in dioxane (2 mL) at 5° C.and stirred at RT for 6 h. After completion, solvent was evaporated, thesolid residue was triturated with Et₂O (10 mL) and dried to afford4-aminocyclohexanone hydrochloride (150 mg, 100%) as off-white solid.The crude was carried to next step without further purification.

Intermediate AL: N-(4-oxocyclohexyl)methanesulfonamide

Methane sulphonyl chloride (1.83 g, 16.07 mmol) was added dropwise to asolution of 4-aminocyclohexanone hydrochloride (Intermediate AK, 1.5 g,13.39 mmol) and K₂CO₃ (6.46 g, 46.87 mmol) in ACN-THF (1:1) (30 mL), andthen stirred at RT for 16 h. After completion, solvent was evaporated,crude residue was diluted with water (50 mL), extracted with EtOAc (2×50mL). The combined extracts were washed with water (50 mL), brine (50mL), dried over anhydrous Na₂SO₄, filtered and evaporated to affordN-(4-oxocyclohexyl) methane sulfonamide (990 mg, 38.6%) as white solid.

Intermediate AM: (R)-tert-butyl(1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolidin-3-yl)carbamate

1,4-dioxaspiro[4.5]decan-8-one (0.76 g, 4.88 mmol) was added to asolution of (R)-tert-butyl pyrrolidin-3-ylcarbamate (1.0 g, 5.36 mmol)in DCE (65 mL) and stirred for 15 mins. Sodium triacetoxy borohydride(1.55 g, 7.32 mmol) was then added at 0° C. and stirred at RT for 16 h.After completion, the reaction mixture was diluted with DCM (50 mL),washed with saturated NaHCO₃ solution (50 mL), water (50 mL), brine (50mL) dried over anhydrous Na₂SO₄, filtered and evaporated. The cruderesidue was purified by column chromatography using SiO₂ by elutingHexane: Methyl tert-butyl ether (80:20) to afford (R)-tert-butyl(1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolidin-3-yl)carbamate (1.53 g,96.8%).

Intermediate AN: (R)-4-(3-aminopyrrolidin-1-yl)cyclohexanone

HCl in 1, 4 dioxane (5 mL) was added to a solution of (R)-tert-butyl(1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolidin-3-yl)carbamate(Intermediate AM, 1.53 g, 8.39 mmol) in dioxane (25 mL) at 15° C. andstirred at RT for 16 h. After completion, saturated Na₂CO₃ solution (50mL) was added, the solvent was evaporated and the residue was trituratedwith Et₂O and dried to afford(R)-4-(3-aminopyrrolidin-1-yl)cyclohexanone (0.61 g, 71.5%).

Intermediate AO: (R)-tert-butyl (1(4-oxocyclohexyl)pyrrolidin-3-yl)carbamate

Di-t-butyl dicarbonate (1.77 g, 9.98 mmol) was added to a solution of(R)-4-(3-aminopyrrolidin-1-yl)cyclohexanone (0.61 g, 3.34 mmol) in water(6 mL) and stirred at RT for 2 hours. After completion, the reactionmixture was washed with DCM (50 mL) and AcOEt (50 mL). The organic layerwas then washed with H2O (50 mL) and brine (50 mL) dried over anhydrousNa₂SO₄, filtered and evaporated. The crude residue was purified bycolumn chromatography using SiO₂ by eluting Hexane: Methyl tert-butylether (80:20) to afford (R)-tert-butyl(1-(4-oxocyclohexyl)pyrrolidin-3-yl)carbamate (0.23 g, 23.9%).

Intermediate AP: 1-ethyl-3-(4-oxocyclohexyl)urea

Isocyanatoethane (237 mg, 3.34 mmol) and triethylamine (0.85 mL, 6.68mmol) was added to a solution of 4-aminocyclohexanone hydrochloride(Intermediate AK, 500 mg, 3.34 mmol) in toluene (5 mL) and stirred at110° C. for 16 h. After completion, the solvent was evaporated, thecrude residue was purified by column chromatography (SiO₂) usingEtOAc:petroleum ether (3:7) to afford 1-ethyl-3-(4-oxocyclohexyl) urea(600 mg, 98%) as a brown solid.

Intermediate AQ: 4-((2-methoxyethoxy)methoxy)benzaldehyde

4-Hydroxybenzaldehyde (50 g, 409 mmol) in THF (50 mL) was added dropwiseand slowly over a period of 30 min to a suspension of sodium hydride(19.6 g, 817 mmol) in THF (750 mL) at 0° C. and stirred for 15 min,followed by addition of 1-(chloromethoxy)-2-methoxyethane (MEM chloride,61.10 g, 490 mmol) at 0° C. The reaction mixture was stirred at RT for30 min and, after completion, poured into ice water (500 mL) andextracted with EtOAc (2×750 mL). The combined organic extracts werewashed with ice water (500 mL), brine (500 mL), dried over anhydrousNa₂SO₄, filtered and concentrated affording4-((2-methoxyethoxy)methoxy)benzaldehyde (52 g, 50%) as a pale yellowliquid. The crude was used in the next step without furtherpurification.

Intermediate AR: (Trans)-2-(4-bromophenyl)cyclopropanamine

To a solution of tert-butyl trans-2-(4-bromophenyl)cyclopropylcarbamate(Intermediate R, 10 g, 32.05 mmol) in 1,4-dioxane (100 mL) at 10° C. wasadded HCl in dioxane (50 mL) and stirred at RT for 20 h. Aftercompletion, the solvent was evaporated and the residue was taken up inice water, basified with saturated aq. NaHCO₃ and extracted with EtOAc(2×100 mL). The combined extracts were washed with water, brine, driedover anhydrous Na₂SO₄, filtered and concentrated to afford(trans)-2-(4-bromophenyl)cyclopropanamine (6.2 g, 91%). The crudeproduct was used in the next step without further purification.

Intermediate AS: Tert-butyl (4-((trans)-2(4-bromophenyl)cyclopropyl)amino)cyclohexyl)carbamate

Tert-butyl 4-oxocyclohexylcarbamate (5 g, 23.58 mmol) was added to asolution of (trans)-2-(4-bromophenyl)cyclopropanamine (Intermediate AR,5 g, 23.58 mmol) in DCE (100 mL) followed by the addition of AcOH (1.41g, 23.58 mmol). The mixture was stirred for 5 min and then cooled to 0°C. before sodium triacetoxy borohydride (8.9 g, 42.45 mmol) was added.The reaction mixture was stirred at RT for 16 h and, after completion,poured into sat. aq. NaHCO₃ and extracted with DCM (2×100 mL). Thecombined extracts were washed with water (100 mL), brine (100 mL), driedover anhydrous Na₂SO₄, filtered and concentrated. The crude residue waspurified by column chromatography (SiO₂, petroleum ether/EtOAc 7:3) toafford tert-butyl (4-(((trans)-2-(4-bromophenyl)cyclopropyl)amino)cyclohexyl)carbamate (6.2 g, 64%).

Intermediate AT: Tert-butyl((trans)-2-(4-bromophenyl)cyclopropyl)(4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate

A NaOH solution (1.96 g, 49 mmol) was added to a solution of tert-butyl(4-(((trans)-2-(4-bromophenyl)cyclopropyl)amino)cyclohexyl)carbamate(Intermediate AS, 5 g, 12.25 mmol) in 1,4-dioxane/H₂O 9:1 (100 mL)followed by Boc anhydride (4 g, 18.37 mmol). The reaction mixture wasstirred at RT for 16 h and, after completion, poured into water (50 mL)and extracted with EtOAc (2×50 mL). The combined extracts were washedwith water (50 mL), brine (50 mL), dried over anhydrous Na₂SO₄, filteredand concentrated. The crude residue was purified by columnchromatography (SiO₂, EtOAc/petroleum ether 2:8) affording tert-butyl((trans)-2-(4-bromophenyl)cyclopropyl)(4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate (5.2 g, 83%) as a colorless liquid.

Intermediate AU: (Trans)-2-(6-bromopyridin-3-yl)cyclopropanamine

This compound was synthesized by following the method described inIntermediate AR and utilizing the respective starting material(tert-butyl ((trans)-2-(6-bromopyridin-3-yl)cyclopropyl)carbamate)leading to 1.2 g of the title compound.

Intermediate AV: (2-bromo-1-fluoroethyl)benzene

Triethylamine trihydrofluoride (36.3 mL, 216.01 mmol) andN-bromosuccinimide (30.75 g, 172.8 mmol) was added to a solution ofstyrene (15 g, 144.0 mmol) in DCM (150 mL) at 0° C. and stirred at RTfor 16 h. After completion, the reaction mixture was neutralized with aqNH₄OH solution (150 mL) and extracted with DCM (2×200 mL). The combinedextracts were washed with 0.1 N HCl solution (100 mL), 5% NaHCO₃solution (100 mL), brine (100 mL) and dried over anhydrous Na₂SO₄,filtered and concentrated to afford (2-bromo-1-fluoroethyl) benzene (25g, 85%) as a brown liquid.

Intermediate AW: (1-fluorovinyl)benzene

KOtBu (27.77 g, 247.54 mmol) was added portionwise to a solution of(2-bromo-1-fluoroethyl)benzene (Intermediate AV, 25 g, 123.7) in pentane(250 mL) at 0° C. The reaction mixture was stirred at reflux temperaturefor 1 h and, after completion, cooled to RT, then poured into ice water(150 mL) and extracted with hexane (2×200 mL). The combined extractswere washed with 5% NaHCO₃ solution (150 mL), 0.05 M HCl solution (150mL), water (150 mL), brine (150 mL) and dried over anhydrous Na₂SO₄,filtered and concentrated to afford (1-fluorovinyl)benzene (13 g, 86%)as a pale yellow liquid.

Intermediate AX: Ethyl 2-fluoro-2-phenylcyclopropanecarboxylate(cis/trans)

Copper(II) acetylacetonate (321 mg, 1.23 mmol) was dissolved in dry DCM(10 mL) and stirred for few min, before a few drops of phenyl hydrazinewere added. The solution was stirred at RT for 10 min, then a solutionof (1-fluorovinyl)benzene (Intermediate AW, 5 g, 40.98 mmol) in dry DCM(50 mL) was added. The mixture was heated to reflux, before a solutionof ethyl diazoacetate (6.46 ml, 61.47 mmol) in CH₂Cl₂ was added dropwiseand slowly for 60 min. The reaction mixture was stirred at refluxtemperature for 14 h and, after completion, cooled to room temperature,diluted with DCM (50 ml), washed with Na₂CO₃ solution (25 mL), water (25mL), and brine (25 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude residue was purified by column chromatography(SiO₂) using DCM: Hexane (10:90) to afford ethyl2-fluoro-2-phenylcyclopropanecarboxylate (cis) (540 mg, 6.3%) and ethyl2-fluoro-2-phenylcyclopropanecarboxylate (trans) (480 mg, 5.6%).

Intermediate AY: (Cis)-ethyl 2-phenylcyclopropanecarboxylate

Ethyl diazo acetate (10.09 mL, 96.01 mmol) was added to a solution ofstyrene (10 g, 96.01 mmol) in dry chloroform (200 mL) followed byCu(I)CI (catalytic) and stirred at 60° C. for 4 h. After completion, thesolvent was evaporated and the crude residue was purified by columnchromatography (SiO₂, EtOAc/petroleum ether 1:9) affording (cis)-ethyl2-phenylcyclopropanecarboxylate (1.7 g, 9.3%) as a colorless liquid.

Intermediate AZ: N-(3-bromo-4-methoxyphenyl)methanesulfonamide

Methanesulphonyl chloride (55.82 mL, 0.494 mmol) was added to a solutionof 3-bromo-4-methoxyaniline (100 mg, 0.494 mmol) in pyridine (1 mL) at0° C. and stirred at RT for 2 h. After completion, reaction mixture waspoured into ice water (10 mL) and extracted with EtOAc (2×15 mL). Thecombined extracts were washed with water (3×10 mL), brine (15 mL) anddried over anhydrous Na₂SO₄ filtered, and evaporated. The crude residuewas purified by column chromatography (SiO₂) by using EtOAc:Hexane (3:7)to afford N-(3-bromo-4-methoxyphenyl)methanesulfonamide (137 mg, 99%) asa white solid.

Intermediate BA:N-(4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide

A solution of N-(3-bromo-4-methoxyphenyl)methanesulfonamide IntermediateAZ, 136 mg, 0.485 mmol), bis(pinacolato)diboron (147 mg, 0.58 mmol) andKOAc (87.3 mg, 0.888 mmol) in dioxane (5.5 mL) was degassed for 30 min,then PdCl₂(dppf)₂ (17.7 mg, 0.020 mmol) was added and the reactionmixture was heated at 100° C. for 3 h. After completion, the reactionmixture was poured into water (10 mL), extracted with EtOAc (2×15 mL).The combined extracts were washed with water (10 mL), brine (50 mL),dried over anhydrous Na₂SO₄, filtered and evaporated. The crude residuewas purified by column chromatography (SiO₂, EtOAc:petroleum ether 1:9)to afford N-(4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (100 mg, 63%) as a white solid.

Intermediate BB:3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

This compound was synthesized by following the method described inIntermediate BA and utilizing the respective starting material(3-bromo-5-methoxybenzonitrile) leading to 1.4 g of the title compoundas a white solid.

Intermediates BC ((Trans)-ethyl2-(5-bromothiophen-2-yl)cyclopropanecarboxylate), BD ((Trans)-ethyl2-(2-bromothiazol-5-yl)cyclopropanecarboxylate) and BE ((Trans)-ethyl2-(4-((2-methoxyethoxy)methoxy)phenyl)cyclopropanecarboxylate)

These intermediates were synthesized by following the same method asdescribed to obtain Intermediate T (Nicotinaldehyde was subjected toHorner-Wadsworth-Emmons reaction to get Intermediate S, which are thensubjected to cyclopropanation reaction leading to Intermediate T)starting from the respective commercially available aldehyde listedbelow:

Starting aldehyde Intermediate

Intermediates BF ((Trans)-2-(5-bromothiophen-2-yl)cyclopropanamine), BG((Trans)-2-(2-bromothiazol-5-yl)cyclopropanamine), BH(4-((trans)-2-aminocyclopropyl)phenol), BI((Cis)-2-fluoro-2-phenylcyclopropanamine), BJ((Trans)-2-fluoro-2-phenylcyclopropanamine)) and BK((Cis)-2-phenylcyclopropanamine)

These intermediates were synthesized by following the same methoddescribed to obtain Intermediate X from Intermediate T (Hydrolisis of(trans)-ethyl 2-(pyridin-3-yl)cyclopropanecarboxylate to getIntermediate U, which are then subjected to Curtius reaction leading,first to Intermediate V and later to intermediate W and finalBoc-deprotection leads to Intermediate X) by using the respectiveintermediates.

Intermediates BF, BH and BK were obtained as hydrochloride salt.

Intermediates BG, BI and BJ were basified with saturated NaHCO₃ aq.solution after acidic treatment at Boc-deprotection step and wereobtained as free base.

Starting intermediate Intermediate ¹H-NMR and MS data

¹HNMR (400 MHz, DMSO-d6 D₂O Exchange) δ (ppm): 7.05 (s, 1H), 6.75 (s,1H), 2.82-2.78 (m, 1H), 2.48-2.42 (m, 1H), 1.42-1.38 (m, 1H), 1.28 (q, J= 6.4 Hz, 1H); Mass (M + H): 217.94

1HNMR (400 MHz, DMSO-d6 D2O Exchange) δ (ppm): 7.48 (s, 1H), 2.9-2.85(m, 1H), 1.50-1.40 (m, 1H), 1.40-1.32 (m, 1H); Mass (M + H):218.91/220.92

1HNMR (400 MHz, D2O) δ (ppm): 7.13 (d, J = 7.6 Hz, 2H), 6.88 (d, J = 7.6Hz, 2H), 2.87-2.80 (m, 1H), 2.44-2.38 (m, 1H), 1.44-1.37 (m, 1H),1.36-1.26 (m, 1H).

The crude was carried to next step without further purification

The crude was carried to next step without further purification

1HNMR (400 MHz, D2O) δ (ppm): 7.44-7.34 (m, 4H), 2.98-2.90 (m, 1H),2.62-2.54 (m, 1H), 1.43-1.35 (m, 1H), 1.34-1.26 (m, 1H); Mass (M + H):134.08

Intermediate BL: Tert-butyl((trans)-2-(4-hydroxyphenyl)cyclopropyl)carbamate

K₂CO₃ (20.36 g, 147.56 mmol) and (Boc)₂O (16.8 mL, 70.27 mmol) was addedto a solution of 4-((trans)-2-aminocyclopropyl)phenol hydrochloride(Intermediate BI, 13 g, 70.27 mmol) in 1,4-dioxane (78 mL) and water(195 mL) and stirred at RT for 16 h. After completion, the reactionmixture was poured into water (300 mL) and extracted with EtOAc (2×200mL). The combined extracts were washed with water (75 mL), brine (75mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The cruderesidue was purified by column chromatography (SiO₂, EtOAc/petroleumether 3:7) affording tert-butyl((trans)-2-(4-hydroxyphenyl)cyclopropyl)carbamate (14 g, 80%) as a brownthick viscous liquid.

Intermediates BM (Tert-butyl(4-(((trans)-2-(6-bromopyridin-3-yl)cyclopropyl)amino)cyclohexyl)carbamate)BN (Tert-butyl(4-(((trans)-2-(5-bromothiophen-2-yl)cyclopropyl)amino)cyclohexyl)carbamate)and BO (Tert-butyl(4-(((trans)-2-(2-bromothiazol-5-yl)cyclopropyl)amino)cyclohexyl)carbamate)

These intermediates were synthesized by following the same method asdescribed to obtain Intermediate AS from Intermediate AR (reductivealkylation) by using the respective starting intermediate.

Starting intermediate Intermediate

Intermediates BP (tert-butyl((trans)-2-(6-bromopyridin-3-yl)cyclopropyl)(4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate)and BQ (tert-butyl((trans)-2-(2-bromothiazol-5-yl)cyclopropyl)(4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate)

These intermediates were synthesized by following the same methoddescribed to obtain Intermediate AT from Intermediate AS(Boc-protection) by using the respective starting intermediate.

Starting intermediate Intermediate

Intermediate BR: tert-butyl((trans)-2-(3′-amino-[1,1′-biphenyl]-4-yl)cyclopropyl)(4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate

A solution of((trans)-2-(4-bromophenyl)cyclopropyl)(4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate (Intermediate AT, 1.5 g, 3.32 mmol),(3-aminophenyl)boronic acid (484 mg, 2.35 mmol) and K₂CO₃ (805 mg, 5.88mmol) in ACN—H₂O 8:2 (20 vol) was degassed for 15 min, before Pd(PPh₃)₄(68 mg, 0.06 mmol) was added. The reaction mixture was stirred at 90° C.for 16 h and, after completion, poured into ice water and extracted withEtOAc (2×50 mL). The combined extracts were washed with water (50 mL),brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated.The crude residue was purified by column chromatography (SiO₂,EtOAc:petroleum ether 3:7) affording tert-butyl((trans)-2-(3′-amino-[1,1′-biphenyl]-4-yl)cyclopropyl)(4-((tert-butoxycarbonyl)amino)cyclohexyl) carbamate (1.23 g, 71%) as a gummy solid.

Intermediates BS(N-(4′-((trans)-2-aminocyclopropyl)-6-methoxy-[1,1′-biphenyl]-3-yl)methanesulfonamide),BT(3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-methoxybenzonitrile)and BU (5-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-2-methylphenol)

These intermediates were synthesized by following the same methoddescribed to obtain Intermediate R from intermediate AH (Suzuki couplingof Intermediate R with 3-(trifluoromethyl)phenylboronic acid to getIntermediate AG and later Boc-deprotection leads to Intermediate R) byusing the respective starting intermediate and commercially available orboronic acid or ester derivatives listed below.

These intermediates were obtained as hydrochloride salt.

Starting intermediate Intermediate ¹H-NMR and MS data

1HNMR (400 MHz, DMSO-d6) δ (ppm): 9.47 (s, 1H), 8.40-8.32 (brs, 3H),7.38 (d, J = 8.4 Hz, 2H), 7.22-7.16 (m, 3H), 7.15-7.05 (m, 2H), 3.73 (s,3H), 2.92 (s, 3H), 2.88-2.82 (brs, 1H), 2.38-2.30 (m, 1H), 1.44-1.36 (m,1H), 1.30-1.22 (m, 1H); Mass (M + H): 331.3

1HNMR (400 MHz, D2O) δ (ppm): 9.65 (s, 1H), 8.26 (brs, 1H), 8.13-8.08(m, 1H), 7.78-7.70 (m, 1H), 7.65-7.59 (m, 1H), 7.57-7.50 (m, 1H), 3.89(s, 3H), 3.20-3.10 (m, 1H), 2.75-2.65 (m, 1H), 1.74-1.65 (m, 1H),1.64-1.55 (m, 1H); Mass (M + H): 266.2

1HNMR (400 MHz, D2O) δ (ppm): 8.54 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H),8.10 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.28-7.20 (m, 1H),3.12-3.08 (m, 1H), 2.68-2.62 (m, 1H), 2.24 (s, 3H), 1.70-1.60 (m, 1H),1.59-1.48 (m, 1H); Mass (M + H): 241.0

Example 1: N1-((trans)-2-phenylcyclopropyl)cyclohexane-1,4-diaminedihydrochloride

Step 1:

Acetic acid (586 mg, 9.77 mmol) was added to a solution oftrans-2-phenylcyclopropanamine (1.3 g, 9.77 mmol) and tert-butyl4-oxocyclohexylcarbamate (2.08 g, 9.77 mmol) in DCE (26 mL) and stirredfor 5 mins. Sodium triacetoxy borohydride (3.72 g, 17.5 mmol) was thenadded at 0° C. and stirred at RT for 5 h. After completion, the reactionmixture was diluted with DCM (50 mL), water (50 mL), brine (50 mL) driedover anhydrous Na₂SO₄, filtered and evaporated. The crude residue waspurified by column chromatography using SiO₂ by eluting EtOAc:Petroleumether (1:9) to afford tert-butyl 4-(trans-2-phenylcyclopropylamino)cyclohexyl carbamate (2.5 g, 77.6%) as a pale yellow liquid.

Step 2:

HCl in 1, 4 dioxane (10 mL) was added to a solution of tert-butyl4-(trans-2-phenylcyclopropylamino) cyclohexyl carbamate (2.45 g, 7.57mmol) in dioxane (25 mL) at 15° C. and stirred at RT for 16 h. Aftercompletion, the solvent was evaporated and the residue was trituratedwith Et₂O and dried to affordN1-((trans)-2-phenylcyclopropyl)cyclohexane-1,4-diamine dihydrochloride(1.5 g, 67.5%) as off white solid.

¹HNMR (400 MHz, DMSO-d6) δ (ppm): 9.66-9.56 (brd, 2H), 8.15-8.11 (d,3H), 7.32-7.16 (m, 5H), 3.33 (brs, 1H), 3.24-3.16 (m, 1H), 2.99 (brs,1H), 2.91 (brs, 1H), 2.55 (brs, 1H), 2.17 (brs, 1H), 2.0 (m, 1H),1.96-1.75 (m, 4H), 1.63-1.43 (m, 2H), 1.4-1.3 (m, 1H), 1.29-1.26 (m,1H); Mass (M+H): 231.34

N1-((trans)-2-phenylcyclopropyl)cyclohexane-1,4-diamine obtained aboveis a mixture of 4 isomers, which correspond to the combination of thetwo different (trans) conformations regarding the cyclopropyl ring(which are (1R,2S) and (1S,2R), respectively) with the CIS and TRANSconformations regarding the cyclohexane ring. The synthesis of each ofthese single isomers was performed as follows:

Example 2: (cis)-N1-((1S,2R)-2-phenylcyclopropyl)cyclohexane-1,4-diaminehydrochloride

Step 1:

To a solution of trans-2-phenylcyclopropanamine (1.1 g, 8.2 mmol) inEtOH (6 mL) at 0° C., added D(−)Tartaric acid (1.24 g, 8.2 mmol), at 0°C. and stirred at RT for 1 h. After completion, solid was filtered anddried to afford trans-2-phenylcyclopropanamine as tartrate salt (2.15 g,91.8%). The salt was taken in isopropanol (IPA):water (3:1) (20 mL) andstirred at 70° C. for 2 h. The clear solution was allowed to cool to RT.The solid separated was collected by filtration, taken in water (50 mL),basified with NaOH solution and extracted with EtOAc (2×50 mL). Thecombined extracts were washed with water (50 mL), brine (50 mL), driedover anhydrous Na₂SO₄, filtered and evaporated to afford(1S,2R)-2-phenylcyclopropanamine (510 mg, 46.3%).

Step 2:

To a solution of (1S,2R)-2-phenylcyclopropanamine (450 mg, 3.38 mmol),tert-butyl 4-oxocyclohexylcarbamate (792 mg, 3.72 mmol) and acetic acid(202 mg, 3.38 mmol) in DCE (10 mL) at 0° C. added sodium triacetoxyborohydride (1.29 g, 6.09 mmol) and stirred at RT for 3 h. Aftercompletion, solvent was evaporated, crude residue was taken in water (25mL) basified with NaHCO₃, and extracted with EtOAc (2×25 mL). Thecombined extracts were washed with water (25 mL), brine (25 mL), driedover anhydrous Na₂SO₄, filtered and evaporated. The crude was purifiedby column chromatography using SiO₂ by eluting EtOAc:pet ether (3:7) toafford tert-butyl((trans)-4-(((1S,2R)-2-phenylcyclopropyl)amino)cyclohexyl)carbamate (210mg, 18.8%) and tert-butyl((cis)-4-(((1S,2R)-2-phenylcyclopropyl)amino)cyclohexyl)carbamate (280mg, 25.1%).

Step 3:

To a solution of tert-butyl((cis)-4-(((1S,2R)-2-phenylcyclopropyl)amino)cyclohexyl)carbamate (190mg, 0.57 mmol) in 1, 4 dioxane (2 mL) at 10° C. added HCl in 1, 4dioxane (2 mL) dropwise and stirred at RT for 16 h. After completionsolvent was evaporated, the solid was stirred with Et₂O, filtered anddried to afford (cis)-N1-((1S,2R)-2-phenylcyclopropyl) cyclohexane-1,4-diamine hydrochloride (110 mg, 71.89%) as off white solid.

¹HNMR (400 MHz, DMSO-d6) δ: 9.5 (brs, 2H), 8.12 (brs, 3H), 7.17-7.32 (m,5H), 3.24 (brs, 2H), 2.98 (brs, 1H), 2.57 (brs, 1H), 1.98-1.74 (m, 8H),1.61 (brs, 1H), 1.28 (m, 1H); Mass (M+H): 231.27; [α]_(D) ²⁸: +57.50(C=0.54% in DMSO).

Example 3:(trans)-N1-((1S,2R)-2-phenylcyclopropyl)cyclohexane-1,4-diaminehydrochloride

This compound was synthesized following the same procedure described inexample 2 but performing the Boc-deprotection reaction to tert-butyl((trans)-4-(((1S,2R)-2-phenylcyclopropyl)amino)cyclohexyl)carbamate asintermediate in Step 3, affording 120 mg (yield=59.4%) as off-whitesolid.

¹H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.52 (brs, 2H), 8.03 (brs, 3H),7.33-7.16 (m, 5H), 3.17 (brs, 1H), 2.9 (brm, 2H), 2.16 (brs, 2H), 2.03(brd, 2H), 1.54-1.25 (m, 6H); Mass (M+H): 231.28; [α]^(28.1) _(D):+67.04° (C=0.53% in DMSO).

Example 4: (cis)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diaminehydrochloride

Step 1:

To a solution of trans-2-phenylcyclopropanamine (crude recovered fromthe mother liquors of the reaction described as Step 1 in Example 2)(0.8 g, 6.01 mmol) in EtOH (5.4 mL) at 0° C., added L (+) tartaric acid(0.90 g, 6.01 mmol), at 0° C. and stirred at RT for 1 h. Aftercompletion, solid was filtered and dried to affordtrans-2-phenylcyclopropanamine as tartrate salt (1.5 g, 88.2%). Salt wastaken in IPA:water (3:1) (15 mL) and stirred at 70° C. for 2 h. Theclear solution was allowed to cool to RT. The solid separated wascollected by filtration, taken in water (50 mL), basified with NaOHsolution, and extracted with EtOAc (2×50 mL). The combined extracts werewashed with water (50 mL), brine (50 mL), dried over anhydrous Na₂SO₄,filtered and evaporated to afford (1R,2S)-2-phenylcyclopropanamine (320mg).

Step 2:

To a solution of (1R,2S)-2-phenylcyclopropanamine (280 mg, 1.21 mmol),tert-butyl 4-oxocyclohexylcarbamate (309 mg, 1.45 mmol) and acetic acid(72 mg, 1.21 mmol) in DCE (8 mL) at 0° C., added sodium triacetoxyborohydride (461 mg, 2.17 mmol) and stirred at RT for 3 h. Aftercompletion, solvent was evaporated, crude residue was taken in water (25mL), treated with NaHCO₃, and extracted with EtOAc (2×25 mL). Thecombined extracts were washed with water (25 mL), brine (25 mL), driedover anhydrous Na₂SO₄, filtered and evaporated. The crude was purifiedby column chromatography using SiO₂ by eluting EtOAc:pet ether (3:7) toafford tert-butyl((cis)-4-(((1R,2S)-2-phenylcyclopropyl)amino)cyclohexyl)carbamate (180mg, 25.35%) and tert-butyl((trans)-4-(((1R,2S)-2-phenylcyclopropyl)amino)cyclohexyl)carbamate (210mg, 29.5%).

Step 3:

To a solution of tert-butyl((cis)-4-(((1R,2S)-2-phenylcyclopropyl)amino)cyclohexyl)carbamate (160mg, 0.48 mmol) in 1, 4 dioxane (2 mL) at 10° C. added HCl in 1, 4dioxane (2 mL) dropwise and stirred at RT for 16 h. After completionsolvent was evaporated, the solid was stirred with Et₂O, filtered anddried to afford(cis)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diaminehydrochloride (80 mg, 58.3%) as off white solid.

¹HNMR (400 MHz, DMSO-d6) δ: 9.54 (brs, 2H), 8.14 (brs, 3H), 7.35-7.15(m, 5H), 3.33 (brs, 1H), 3.25 (brs, 2H), 2.62-2.55 (m, 1H), 2.03-1.67(m, 8H), 1.63-1.57 (m, 1H), 1.28 (q, 1H); Mass (M+H): 231.27; [α]_(D)^(28.5): −65.70° (C=0.5% in DMSO).

Example 5:(trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diaminehydrochloride

This compound was synthesized following the same procedure described inexample 4 but performing the Boc-deprotection reaction to tert-butyl((trans)-4-(((1R,2S)-2-phenylcyclopropyl)amino)cyclohexyl)carbamate inStep 3, affording 95 mg (yield=50.8%) as off-white solid.

¹HNMR (400 MHz, DMSO-d6, D2O Exchange) δ (ppm): 7.32 (t, J=7.2 Hz, 2H),7.24 (t, J=7.2 Hz, 1H), 7.17 (d, J=8 Hz, 2H), 3.26-3.18 (m, 1H),3.05-2.89 (m, 2H), 2.51-2.42 (m, 1H), 2.22-2.10 (m, 2H), 2.08-1.98 (m,2H), 1.57-1.28 (m, 6H); Mass (M+H): 231.25; [α]_(D) ^(28.5): −60.19°(C=0.54% in DMSO).

Using an alternative procedure,(trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diamine wasobtained as follows:

To a well stirred solution of (1R,2S)-2-phenylcyclopropanamine (0.752 g5.64 mmol) in methanol (10 ml) at room temperature (22-25° C.),molecular sieves (1.0 g) was added followed byt-butyl-4-oxocyclohexylcarbamate (1.07 g, 5.0 mmol) at 100° C. andstirred for 5 min. Acetic acid (0.028 ml, 0.5 mmol) was added at 0-5° C.to the reaction mixture and stirred for 3 h at room temperature. Thereaction mixture was cooled to −25 to −30° C., and sodium borohydride(0.229 g, 6.02 mmol) was added portionwise at the same temperature. Thereaction mixture was stirred for 3 h allowing the reaction temperatureto rise to room temperature.

The progress of the reaction was monitored by TLC (EtOAc/Hexane 8:2).After completion of reaction, the inorganics were filtered off overcelite. The filtrate was evaporated, and the crude residue was taken upin water (20 ml) and DCM (20 ml) mixture and basified with 5% aq. NaOHsolution (until pH 10). The DCM layer was separated and the aq. layerre-extracted with DCM (20 ml). The combined organic extracts were washedwith water (20 ml) and 10% brine solution (20 ml), dried over anhydroussodium sulfate, filtered and evaporated completely. The crude productwas purified by stirring in 2% EtOAc in hexane for 2 h at roomtemperature to affordt-butyl-4-((1R,2S)-2-phenylcyclopropylamino)cyclohexylcarbamate asoff-white solid (0.90 g, 54%).

To a well stirred solution oft-butyl-4-((1R,2S)-2-phenylcyclopropylamino) cyclohexylcarbamate (0.8 g,2.42 mmol) in 1, 4-dioxane (10 ml) at 10-15° C. was slowly added 15% HClin dioxane (8 ml) and stirred at room temperature for 20 h. The progressof the reaction was monitored by HPLC. After completion of the reaction,the solvent was removed at reduced pressure. The residue was suspendedin di-isopropyl ether (15 ml) and stirred for 1 h at room temperature,filtered and dried in vacuo. The crude product was further purified bystirring in di-isopropyl ether (15 ml) for 2 h at room temperature. Thesolid was filtered off affording(trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclohexane-1,4-diaminedihydrochloride (0.57 g, 77%) (the presence of the dihydrochloride saltform was determined by argentometric titration), as an off white solid.

¹HNMR (400 MHz, DMSO-d6) δ (ppm): 9.74 (bs, 2H), 8.18 (bs, 3H), 7.30 (m,2H), 7.24 (m, 1H), 7.18 (m, 2H), 3.15 (bs, 1H), 2.94 (m, 2H), 2.56 (m,1H), 2.18 (m, 2H), 2.04 (m, 2H), 1.58 (m, 3H), 1.44 (m, 2H), 1.26 (m,1H); Mass (M+H): 231.5

The following compounds can be synthesized following the methodologydescribed for example 1 by using the corresponding intermediates. TheStep 2 was only performed in case the intermediate used in the reductivealkylation (Step 1) contained a Boc (tert-butyloxycarbonyl) protectinggroup.

Example 6:N1-((trans)-2-(thiazol-5-yl)cyclopropyl)cyclohexane-1,4-diaminehydrochloride

¹HNMR (400 MHz, DMSO-d6-D₂O Exchange) δ (ppm): 8.95 (s, 1H), 7.75 (s,1H), 3.3-3.18 (m, 1H), 3.1-2.9 (m, 2H), 2.85-2.72 (m, 1H), 2.25-1.98(brm, 3H), 1.7-1.35 (brm, 5H); Mass (M+H): 238.19

Example 7:N1-((trans)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diaminehydrochloride

¹HNMR (400 MHz, D₂O) δ (ppm): 8.64 (2H, d), 8.32 (1H, d), 7.98 (1H, t),3.37 (2H, m), 3.22 (2H, m), 2.77-2.72 (1H, m), 2.25-2.12 (3H, m),1.92-1.46 (7H, m), Mass (M+H): 232.34

Example 8:N1-((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diaminehydrochloride

¹HNMR (400 MHz, D₂O) δ (ppm): 8.60 (s, 1H), 8.20-8.00 (m, 3H), 7.90 (d,J=12 Hz, 1H), 7.76-7.72 (t, J=8 Hz, 1H), 7.60-7.40 (br, 1H), 3.60-3.40(m, 2H), 3.20 (m, 1H), 2.70 (m, 1H), 2.30 (m, 1H), 2.20-2.00 (m, 2H),1.97-1.67 (m, 5H), 1.65 (m, 1H), 1.60-1.40 (m, 1H); Mass (M+H): 376.3

Example 9: N1-((trans)-2 (3′(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diaminehydrochloride

¹HNMR (400 MHz, DMSO d6) δ: 9.65-9.48 (brd, 2H), 8.1 (s, 3H), 7.95 (m,2H), 7.7 (m, 4H), 7.3 (d, 2H), 3.2 (brd, 1H), 2.9 (brd, 2H), 2.52 (m,1H), 2.2 (brd, 2H), 2.05 (brd, 2H), 1.86-1.76 (m, 2H), 1.6-1.25 (m, 5H);Mass (M+H): 375.29

Example 10:N1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)cyclohexane-1,4-diaminehydrochloride

¹HNMR (400 MHz, DMSO d6) δ: 9.64-9.45 (brd, 2H), 8.2-8.05 (brd, 3H),7.48-7.3 (m, 5H), 7.15 (d, 2H), 6.95 (d, 2H), 5.08 (s, 2H), 3.2-3.15(brs, 1H), 2.9 (brs, 1H), 2.82 (brs, 1H), 2.45 (brs, 1H), 2.18 (brd,2H), 2.05 (brd, 2H), 1.9 (brs, 1H), 1.58-1.27 (m, 4H), 1.22 (m, 1H);Mass (M+H): 337.31

Example 11:4-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)cyclohexanol

¹HNMR (400 MHz, D₂O) δ (ppm): 8.76 (s, 1H), 8.37 (brs, 1H), 8.32-8.26(m, 2H), 8.16 (m, 1H), 8.06 (m, 1H), 7.91 (t, J=8 Hz, 1H), 4.11 (brs,1H), 3.84-3.65 (m, 1H), 3.60-3.40 (m, 1H), 3.33 (brs, 1H), 2.87 (brs,1H), 2.28-2.03 (m, 3H), 1.90-1.70 (m, 4H), 1.68-1.57 (m, 1H), 1.55-1.40(m, 1H); Mass (M+H): 377.2

Example 12:4-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)cyclohexanecarboxamidehydrochloride

¹HNMR (400 MHz, D₂O) δ (ppm): 8.80 (brs, 1H), 8.50-8.40 (brs, 1H),8.38-8.26 (m, 2H), 8.20-8.00 (m, 2H), 7.95-7.83 (m, 1H), 3.65-3.25 (m,3H), 2.96-2.82 (m, 1H), 2.75-2.54 (m, 1H), 2.47-2.30 (m, 1H), 2.20-1.80(m, 7H), 1.70-1.50 (m, 1H); Mass (M+H): 404.3

Example 13:N-(4-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)cyclohexyl)acetamidehydrochloride

¹HNMR (400 MHz, D₂O) δ (ppm): 8.79 (s, 1H), 8.39 (m, 1H), 8.30 (m, 1H),8.24 (s, 1H), 8.13 (m, 1H), 8.11 (m, 1H), 7.88 (t, J=8 Hz, 1H),3.70-3.62 (m, 1H), 3.50-3.40 (m, 1H), 3.38-3.24 (m, 1H), 2.92-2.80 (m,1H), 2.34-2.24 (m, 2H), 2.17-2.03 (m, 3H), 1.98 (s, 1H), 1.94-1.72 (m,4H), 1.70-1.57 (m, 1H), 1.50-1.35 (m, 2H). Mass (M+H): 418.2

Example 14:N-(4-(((trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropyl)amino)cyclohexyl)methanesulfonamidehydrochloride

¹HNMR (400 MHz, D₂O) δ (ppm): 8.73 (s, 1H), 8.41-8.32 (m, 1H), 8.28-8.22(m, 2H), 8.12 (d, J=8 Hz, 1H), 8.03 (d, J=8 Hz, 1H), 7.88 (t, J=8 Hz,1H), 3.3.52-3.26 (m, 3H), 3.14 (s, 3H), 2.91-2.80 (m, 1H), 2.36-1.96 (m,4H), 1.88-1.58 (m, 4H), 1.56-1.42 (m, 2H). Mass (M+H): 454.1

Example 15:(R)-1-(4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl)pyrrolidin-3-aminetrihydrochloride

¹HNMR (400 MHz, DMSO-d6) δ (ppm): 10.71-10.45 (m, 1H), 9.61-9.50 (brs,1H), 9.49-9.34 (brs, 1H), 8.09 (t, J=6 Hz, 3H), 7.98 (quin, 2H),4.85-4.20 (m, 7H), 4.08-3.92 (m, 1H), 3.82-3.65 (m, 1H), 3.47-3.38 (m,1H), 3.10-2.32 (m, 11H), 2.07 (q, 1H). Mass (M+H): 300.1

The following compounds were synthesized following the methodologydescribed for example 1 by using the corresponding intermediates andcommercially available reagents. Step 2 was only applied to thoseintermediates used in the reductive alkylation (Step 1) that contained aBoc (tert-butyloxycarbonyl) protecting group.

Example 16:1-methyl-N4-((trans)-2-phenylcyclopropyl)cyclohexane-1,4-diamine

¹HNMR (400 MHz, D₂O) δ: 7.45-7.30 (m, 3H), 7.24 (d, J=8 Hz, 2H),3.55-3.42 (m, 1H), 3.05-2.98 (m, 1H), 2.62-2.52 (m, 1H), 2.28-2.20 (m,2H), 2.18-1.98 (m, 2H), 1.87-1.64 (m, 4H), 1.62-1.44 (m, 2H), 1.41 (s,3H); Mass (M+H): 245.33. This compound was obtained as hydrochloridesalt.

Example 17: 4-(aminomethyl)-N-trans)-2-phenylcyclopropyl)cyclohexanamine

¹HNMR (400 MHz, CD₃OD) δ: 7.33-7.25 (m, 2H), 7.21-7.17 (m, 3H), 3.45(brs, 1H), 2.98 (d, J=8 Hz, 1H), 2.95-2.92 (m, 1H), 2.82 (d, J=7 Hz,1H), 2.57-2.55 (m, 1H), 2.28-2.26 (m, 1H), 1.95-1.90 (m, 4H), 1.73-1.70(m, 3H), 1.62-1.58 (m, 2H), 1.45-1.39 (m, 1H); Mass (M+H): 245.29. Thiscompound was obtained as hydrochloride salt.

Example 18: N-((trans)-2-phenylcyclopropyl)cyclohexane-1,3-diamine

¹HNMR (400 MHz, DMSO-d6-D₂O Exchange) δ (ppm): 7.33 (t, J=7.4 Hz, 2H),7.26 (d, J=7.2 Hz, 1H), 7.23 (t, J=8 Hz, 2H), 4.1-4.0 (m, 1H), 4.0-3.9(m, 1H), 2.96-2.86 (m, 1H), 2.5-2.43 (m, 1H), 2.10-1.90 (m, 2H),1.88-1.76 (m, 2H), 1.75-1.63 (m, 3H), 1.62-1.48 (m, 2H), 1.40-1.30 (m,1H); Mass (M+H): 231.29. This compound was obtained as hydrochloridesalt.

Example 19: N1-((trans)-2-phenylcyclopropyl)cyclobutane-1,3-diamine

¹HNMR (400 MHz, DMSO-d6-D₂O Exchange) δ (ppm): 7.33 (t, J=8 Hz, 2H),7.25 (t, J=8 Hz, 1H), 7.17 (d, J=8 Hz, 2H), 4.1-4.0 (m, 1H), 2.95-2.85(m, 1H), 2.74-2.60 (m, 2H), 2.5-2.42 (m, 3H), 1.48 (quin, 1H), 1.33 (q,1H); Mass (M+H): 203.0. This compound was obtained as hydrochloridesalt.

Example 20:N1-((trans)-2-phenylcyclopropyl)-2,3-dihydro-H-indene-1,3-diamine

¹HNMR (400 MHz, D₂O) δ: 7.70-7.53 (m, 4H), 7.46-7.30 (m, 3H), 7.17 (d,J=8 Hz, 1H), 7.03 (d, J=8 Hz, 1H), 5.40-5.30 (m, 1H), 5.14-5.04 (m, 1H),3.05-2.93 (m, 2H), 2.78-2.64 (m, 1H), 2.54-2.32 (m, 1H), 1.62-1.42 (m,2H); Mass (M+H): 265.3. This compound was obtained as hydrochloridesalt.

Example 21: N1-((cis)-2-phenylcyclopropyl)cyclohexane-1,4-diamine

¹HNMR (400 MHz, DMSO-d6-D₂O Exchange) δ: 7.46-7.30 (m, 5H), 3.03-2.88(m, 2H), 2.52-2.45 (m, 1H), 2.27-2.20 (m, 1H), 2.08-1.94 (m, 2H),1.94-1.58 (m, 3H), 1.54-1.20 (m, 5H); Mass (M+H): 231.18. This compoundwas obtained as hydrochloride salt.

Example 22:N1-methyl-N4-((trans)-2-phenylcyclopropyl)cyclohexane-1,4-diamine

¹HNMR (400 MHz, D₂O) δ: 7.61-7.34 (m, 3H), 7.30-7.20 (m, 2H), 3.70-3.58(brs, 1H), 3.53-3.33 (m, 1H), 3.22-2.95 (m, 1H), 2.82-2.70 (m, 3H),2.63-2.47 (brs, 1H), 2.42-2.22 (m, 2H), 2.18-1.85 (m, 5H), 1.45-1.65 (m,3H); Mass (M+H): 245.1. This compound was obtained as hydrochloridesalt.

Example 23: Tert-butyl(4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl) carbamate

¹HNMR (400 MHz, CDCl₃) δ (rotamers 1:1): 7.28-7.23 (m, 2H), 7.17-7.13(m, 1H), 7.02 (d, J=8 Hz, 2H), 4.62 (brs, 0.5H), 4.35 (brs, 0.5H), 3.63(brs, 0.5H), 3.39 (brs, 0.5H), 2.79 (brs, 0.5H), 2.69-2.57 (m, 0.5H),2.38-2.22 (m, 1H), 1.98-1.94 (m, 3H), 1.87-1.82 (m, 1H), 1.75-1.60 (m,2H), 1.43 (s, 9H), 1.33-1.00 (m, 5H); Mass (M+H): 331.27. This compoundwas obtained as the free amine.

Example 24:1-ethyl-3-(4-(((trans)-2-phenylcyclopropyl)amino)cyclohexyl)urea

¹HNMR (400 MHz, DMSO-d6-D₂O Exchange) δ: 7.33 (t, J=7.6 Hz, 2H), 7.24(t, J=7.2 Hz, 1H), 7.18 (d, J=8 Hz, 2H), 3.36-3.14 (m, 1H), 3.04-2.92(m, 3H), 2.50-2.40 (m, 2H), 2.12-2.04 (m, 1H), 1.93-1.81 (m, 2H),1.75-1.61 (m, 2H), 1.60-1.40 (m, 3H), 1.39-1.30 (m, 1H), 1.20-1.13 (m,1H), 1.03-0.94 (m, 3H); Mass (M+H): 302.26.

This compound was obtained as hydrochloride salt.

Example 25: 4-morpholino-N-((trans)-2-phenylcyclopropyl)cyclohexanamine

¹HNMR (400 MHz, CDCl₃) δ: 7.28-7.22 (m, 2H), 7.14 (t, J=8 Hz, 1H), 7.02(d, J=8 Hz, 2H), 3.78-3.68 (m, 4H), 2.94-2.85 (m, 1H), 2.53 (brs, 4H),2.30-2.23 (m, 1H), 2.22-2.16 (m, 1H), 1.92-1.84 (m, 1H), 1.70-1.62 (m,2H), 1.61-1.47 (m, 5H), 1.10-1.02 (m, 1H), 1.01-0.96 (m, 1H); Mass(M+H): 301.2. This compound was obtained as the free amine.

Example 26:N1-((trans)-2-(4-bromophenyl)cyclopropyl)cyclohexane-1,4-diamine

¹HNMR (400 MHz, D₂O) δ: 7.56 (d, J=8 Hz, 2H), 7.14 (d, J=8 Hz, 2H),3.64-3.50 (m, 1H), 3.48-3.38 (m, 1H), 2.35-2.24 (m, 1H), 3.05-2.97 (m,1H), 2.60-2.48 (m, 1H), 2.40-2.19 (m, 2H), 2.18-1.84 (m, 3H), 1.70-1.44(m, 4H); Mass (M+H): 309.06. This compound was obtained as hydrochloridesalt.

Example 27: N1-(2-(o-tolyl)cyclopropyl)cyclohexane-1,4-diamine

¹HNMR (400 MHz, CD₃OD) δ: 7.22-7.12 (m, 3H), 7.04-6.98 (m, 1H),3.60-3.40 (m, 1H), 3.22-3.08 (m, 2H), 2.72-2.49 (m, 1H), 2.44 (s, 3H),2.42-2.34 (m, 1H), 2.25-2.16 (m, 1H), 2.15-1.92 (m, 4H), 1.70-1.50 (m,3H), 1.32-1.24 (m, 1H); Mass (M+H): 245.22. This compound was obtainedas hydrochloride salt.

Example 28:N1-(2-(4-(trifluoromethyl)phenyl)cyclopropyl)cyclohexane-1,4-diamine

¹HNMR (400 MHz, DMSO-d6-D₂O Exchange) δ: 7.73-7.63 (m, 2H), 7.50-7.36(m, 2H), 3.26-3.10 (m, 1H), 3.07-2.92 (m, 1H), 2.48-2.41 (m, 1H),2.20-2.09 (m, 2H), 2.08-1.98 (m, 1H), 1.90-1.67 (m, 5H), 1.60-1.32 (m,4H); Mass (M+H): 299.24. This compound was obtained as hydrochloridesalt.

Example 29: N1-(2-(4-methoxyphenyl)cyclopropyl)cyclohexane-1,4-diamine

¹HNMR (400 MHz, CD₃OD) δ: 7.16-7.08 (m, 2H), 6.87 (d, J=8.8 Hz, 4H),3.76 (s, 3H), 3.44-3.38 (m, 1H), 3.22-3.12 (m, 0.5H), 2.94-2.85 (m, 1H),2.52-2.44 (m, 0.5H), 2.43-2.30 (m, 2H), 2.24-2.14 (m, 1H), 2.10-1.90 (m,3H), 1.62-1.51 (m, 3H), 1.50-1.42 (m, 1H), 1.37 (q, 1H); Mass (M+H):261.26. This compound was obtained as hydrochloride salt.

Example 30: 4-(2-((4-aminocyclohexyl)amino)cyclopropyl)phenol

¹HNMR (400 MHz, DMSO-d6-D₂O Exchange) δ: 6.98 (d, J=8.4 Hz, 2H), 6.71(d, J=8.4 Hz, 2H), 3.24-3.15 (m, 1H), 3.07-2.95 (m, 1H), 2.87-2.78 (m,1H), 2.45-2.36 (m, 1H), 2.22-2.11 (m, 2H), 2.09-1.98 (m, 2H), 1.94-1.75(m, 1H), 1.58-1.34 (m, 4H), 1.26-1.18 (m, 1H); Mass (M+H): 247.22. Thiscompound was obtained as a hydrochloride salt.

Example 31: N1-(2-(2-fluorophenyl)cyclopropyl)cyclohexane-1,4-diamine

¹HNMR (400 MHz, CD₃OD) δ: 7.33-7.31 (m, 1H), 7.29-7.26 (m, 3H),3.52-3.30 (m, 2H), 3.17-3.06 (m, 2H), 2.73-2.61 (m, 1H), 2.36-2.33 (m,1H), 2.17-2.20 (m, 1H), 2.05-1.95 (m, 4H), 1.58-1.45 (m, 4H); Mass(M+H): 249.23. This compound was obtained as a hydrochloride salt.

Example 32:N1-(2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1,4-diamine

¹HNMR (400 MHz, CD₃OD) δ: 7.27-7.12 (m, 2H), 7.08-7.00 (m, 1H),3.56-3.46 (m, 1H), 3.46-3.34 (m, 1H), 3.24-3.14 (m, 1H), 3.05-2.97 (m,1H), 2.68-2.60 (m, 1H), 2.58-2.48 (m, 1H), 2.38-2.25 (m, 1H), 2.38-2.25(m, 1H), 2.23-2.15 (m, 1H), 2.14-1.90 (m, 4H), 1.70-1.50 (m, 3H), 1.43(q, 1H); Mass (M+H): 267.21. This compound was obtained as ahydrochloride salt.

Example 33: N1-(2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine

¹HNMR (400 MHz, DMSO-d6-D₂O Exchange) δ: 7.93-7.83 (m, 3H), 7.71 (s,1H), 7.50 (quin, 2H), 7.34 (d, J=8.4 Hz, 1H), 3.28-3.19 (m, 1H),3.10-2.97 (m, 2H), 2.68-2.60 (m, 1H), 2.24-2.15 (m, 2H), 2.08-1.98 (m,2H), 1.62-1.35 (m, 6H); Mass (M+H): 281.14. This compound was obtainedas a hydrochloride salt.

Example 34: N1-(2-methyl-2-phenylcyclopropyl)cyclohexane-1,4-diamine

¹HNMR (400 MHz, CD₃OD) δ: 7.40-7.30 (m, 4H), 7.27-7.21 (m, 1H),3.58-3.46 (m, 1H), 2.95-2.85 (m, 1H), 2.54-2.28 (m, 1H), 2.25-2.18 (m,1H), 2.16-1.92 (m, 5H), 1.67 (s, 3H), 1.62-1.52 (m, 2H), 1.35-1.25 (m,1H); Mass (M+H): 245.22. This compound was obtained as a hydrochloridesalt.

Example 35:(R)-1-(4-(((trans)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)amino)cyclohexyl)pyrrolidin-3-amine

¹HNMR (400 MHz, D₂O) δ: 7.98 (s, 1H), 7.89 (d, J=8 Hz, 2H), 7.76-7.62(m, 3H), 7.2 (d, J=8 Hz, 2H), 4.2 (brs, 2H), 4.06-3.96 (m, 2H),3.72-3.62 (m, 2H), 3.10-3.01 (m, 1H), 2.70-2.56 (m, 2H), 2.34-2.20 (m,2H), 2.18-2.02 (m, 3H), 2.00-1.86 (m, 2H), 1.65-1.55 (m, 2H); Mass(M+H): 444.3. This compound was obtained as hydrochloride salt.

Example 36:(Cis)-N1-((1S,2R)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine

Step 1:

L (+) Mandelic acid (2.7 g, 18.05 mmol) was added to a solution of(trans)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropanamine(free amine derived from Intermediate AH, 5 g, 18.05 mmol) in EtOH/H₂O1:9 (25 vols) and refluxed for 2 h. After formation of a clear solution,the reaction mixture was allowed to cool to RT (16 h). The solid thathad precipitated was filtered off, taken up in water (100 mL), basifiedwith an aq. solution of NaHCO₃ and extracted with EtOAc (2×100 mL). Thecombined extracts were washed with water (100 mL), brine (100 mL), driedover anhydrous Na₂SO₄, filtered and evaporated to afford(1S,2R)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropanamine(1.3 g) as a light yellow solid.

Step 2:

Tert-butyl 4-oxocyclohexylcarbamate (999 mg, 4.69 mmol), acetic acid(280 mg, 4.69 mmol) and sodium triacetoxy borohydride (1.78 g, 8.44mmol) were added to a solution of(1S,2R)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropanamine(1.3 g, 4.69 mmol) in DCE (10 mL) at 0° C. and stirred at RT for 3 h.After completion of the reaction, the solvent was evaporated and thecrude residue was taken up in water (25 mL), washed with NaHCO₃, andextracted with EtOAc (2×25 mL). The combined extracts were washed withwater (25 mL), brine (25 mL), dried over anhydrous Na₂SO₄, filtered andevaporated.

The diasteriomers were separated by flash column chromatography usingSiO₂ by eluting with EtOAc:petroleum ether (3:7). First, the less polartert-butyl((cis)-4-(((1S,2R)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)amino)cyclohexyl)carbamate (460 mg) was isolated followed by the more polar tert-butyl((trans)-4-(((1S,2R)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)amino)cyclohexyl)carbamate (490 mg).

Step 3:

HCl in 1,4-dioxane (5 mL) was added to a solution of tert-butyl((cis)-4-(((1S,2R)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)amino)cyclohexyl)carbamate(440 mg, 0.93 mmol) in 1,4-dioxane (9 mL) at 15° C. and stirred at RTfor 16 h. After completion, the solvent was evaporated. The residue wastriturated with Et₂O, filtered off and dried to afford(cis)-N1-((1S,2R)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamineas hydrochloride salt (320 mg) an off white solid.

¹HNMR (400 MHz, DMSO-d6-D₂O Exchange) δ: 8.02-7.92 (m, 2H), 7.71 (d, J=8Hz, 4H), 7.32 (d, J=8 Hz, 2H), 3.38 (brs, 1H), 3.27 (brs, 1H), 3.06(brs, 1H), 2.60 (brs, 1H), 2.0-1.73 (m, 8H), 1.62 (brs, 1H), 1.44-1.35(m, 1H); Mass (M+H): 375.23; [α]_(D) ^(25.1): +53.93° (C=0.53% in DMSO).

Example 37:(Trans)-N1-((1S,2R)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclo-propyl)cyclohexane-1,4-diamine

This compound was synthesized following the same procedure as describedin example 36 leading to Boc-intermediate tert-butyl((trans)-4-(((1S,2R)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)amino)cyclohexyl)carbamateas a second product in the reductive alkylation step and finallyaffording 328 mg of the title compound as a hydrochloride salt, a palebrown solid.

¹HNMR (400 MHz, DMSO-d6-D₂O Exchange) δ: 8.02-7.92 (m, 2H), 7.71 (d, J=8Hz, 4H), 7.32 (d, J=8 Hz, 2H), 3.30-3.20 (m, 1H), 3.06-2.96 (m, 2H),2.62-2.54 (m, 1H), 2.25-2.15 (m, 2H), 2.10-2.00 (m, 2H), 1.62-1.35 (m,6H); Mass (M+H): 375.25; [α]_(D) ^(25.5): +52.83° (C=0.53% in DMSO).

Example 38:(Cis)-N1-((1R,2S)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclo-propyl)cyclohexane-1,4-diamine

Step 1:

D (−) Mandelic acid (2.7 g, 18.05 mmol) was added to a solution of(trans)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropanamine(free amine derived from Intermediate AH, 5 g, 18.05 mmol) in EtOH/H₂O1: 9 (25 vols) and refluxed for 2 h. After formation of a clearsolution, the reaction mixture was allowed to cool to RT (16 h). Theprecipitated solid was filtered off, taken up in water (100 mL),basified with an aq. solution of NaHCO₃ and extracted with EtOAc (2×100mL). The combined extracts were washed with water (100 mL), brine (100mL), dried over anhydrous Na₂SO₄, filtered and evaporated to afford(1R,2S)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropanamine(900 mg) as a light yellow solid.

Step 2:

Tert-butyl 4-oxocyclohexylcarbamate (692 mg, 3.2 mmol), acetic acid (194mg, 3.2 mmol) and sodium triacetoxy borohydride (1.2 g, 5.76 mmol) wereadded to a solution of(1R,2S)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropanamine(900 mg, 3.2 mmol) in DCE (10 mL) at 0° C. and stirred at RT for 3 h.After completion, the solvent was evaporated. The residue was taken upin water (25 mL), washed with NaHCO₃, and extracted with EtOAc (2×25mL). The combined extracts were washed with water (25 mL), brine (25mL), dried over anhydrous Na₂SO₄, filtered and evaporated.

The diasteriomers were separated by flash column chromatography usingSiO₂ by eluting with EtOAc:petroleum ether (3:7). First, the less polarisomer tert-butyl((cis)-4-(((1R,2S)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)amino)cyclohexyl)carbamate(390 mg) was isolated followed by the more polar isomer tert-butyl((trans)-4-(((1R,2S)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)amino)cyclohexyl)carbamate(480 mg).

Step 3:

HCl in dioxane (4 mL) was added to a solution of tert-butyl((cis)-4-(((1R,2S)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)amino)cyclohexyl)carbamate(380 mg, 0.801 mmol) in 1, 4 dioxane (8 mL) at 15° C. and stirred at RTfor 16 h. After completion, the solvent was evaporated. The residue wastriturated with Et₂O, filtered off and dried to afford(cis)-N1-((1R,2S)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamineas a hydrochloride salt (280 mg), a white solid.

¹HNMR (400 MHz, DMSO-d6-D₂O Exchange) δ: 8.02-7.92 (m, 2H), 7.71 (d, J=8Hz, 4H), 7.33 (d, J=8 Hz, 2H), 3.39 (brs, 1H), 3.28 (brs, 1H), 3.05(brs, 1H), 2.60 (brs, 1H), 2.0-1.75 (m, 8H), 1.68-1.60 (m, 1H),1.46-1.38 (m, 1H); Mass (M+H): 375.28; [α]_(D) ^(28.1): −65.31° (C=0.53%in DMSO).

Example 39:(Trans)-N1-((1R,2S)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclo-propyl)cyclohexane-1,4-diamine

This compound was synthesized following the same procedure as describedin example 38 leading to Boc-intermediate tert-butyl((trans)-4-(((1R,2S)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)amino)cyclohexyl)carbamateas a second product in the reductive alkylation step and finallyaffording 350 mg of the title compound as a hydrochloride salt, a palebrown solid.

¹HNMR (400 MHz, DMSO-d6-D₂O Exchange) δ: 8.02-7.92 (m, 2H), 7.71 (d, J=8Hz, 4H), 7.32 (d, J=8 Hz, 2H), 3.30-3.20 (m, 1H), 3.06-2.96 (m, 2H),2.62-2.54 (m, 1H), 2.25-2.15 (m, 2H), 2.10-2.00 (m, 2H), 1.62-1.35 (m,6H); Mass (M+H): 375.24; [α]_(D) ^(25.8): −48.30° (C=0.52% in DMSO).

Example 40:N1-((trans)-2-(4-cyclopropylphenyl)cyclopropyl)cyclohexane-1,4-diamine

Step 1:

A solution of tert-butyl((trans)-2-(4-bromophenyl)cyclopropyl)(4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate(Intermediate AT, 400 mg, 0.78 mmol), cyclopropyl boronic acid (81 mg,0.94 mmol) and K₂CO₃ (322 mg, 2.34 mmol) in ACN/H₂O 4:1 (8 mL) wasdegassed for 30 min. Pd(PPh₃)₄ (45 mg, 0.039 mmol) was added, and themixture was stirred at reflux temperature for 16 h. After completion,the reaction mixture was poured into water and extracted with EtOAc(2×25 mL). The combined extracts were washed with water (25 mL), brine(25 mL), dried over anhydrous Na₂SO₄, filtered and evaporated. The crudematerial was purified by column chromatography (SiO₂) usingEtOAc:petroleum ether (3:7) to afford tert-butyl(4-((tert-butoxycarbonyl)amino)cyclohexyl)((trans)-2-(4-cyclopropylphenyl)cyclopropyl)carbamate(160 mg) as a white solid.

Step 2:

HCl in dioxane (1 mL) was added to a solution of tert-butyl(4-((tert-butoxycarbonyl)amino)cyclohexyl)((trans)-2-(4-cyclopropylphenyl)cyclopropyl)carbamate(160 mg, 0.33 mmol) in dioxane (3 mL) at 10° C. and stirred at RT for 16h. After completion, the solvent was evaporated. The solid wastriturated with Et₂O, filtered off and dried to affordN1-((trans)-2-(4-cyclopropylphenyl)cyclopropyl)cyclohexane-1,4-diamineas a hydrochloride salt (60 mg), a white solid.

¹HNMR (400 MHz, DMSO d6) δ: 9.50-9.43 (m, 2H), 8.03 (brs, 3H), 7.02-6.98(m, 4H), 3.28-3.18 (m, 1H), 2.97-2.80 (m, 1H), 2.43 (brs, 1H), 2.17(brs, 1H), 2.02-1.75 (m, 6H), 1.58-1.20 (m, 5H), 0.92-0.87 (m, 2H),0.61-0.57 (m, 2H); Mass (M+H): 271.24

The following compounds were synthesized according to the generalmethods disclosed under the General Synthetic Route Description Sectionand in particular by following the method described in example 40 andutilizing the respective intermediates or commercially availablereagents.

Example 41:N1-((trans)-2-(4-(pyridin-3-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine

¹HNMR (400 MHz, DMSO d6) δ: 9.82-9.69 (m, 2H), 9.16 (m, J=12.8 Hz, 1H),8.78 (brs, 1H), 8.68-8.63 (m, 1H), 8.19-8.15 (m, 3H), 7.95-7.92 (m, 1H),7.81 (s, 2H), 7.38 (s, 2H), 3.28-3.08 (m, 2H), 2.99 (brs, 1H), 2.67(brs, 1H), 2.20 (brs, 1H), 2.05-2.02 (m, 1H), 1.98-1.89 (m, 1H),1.78-1.63 (m, 5H), 1.44-1.36 (m, 2H); Mass (M+H): 308.2. This compoundwas obtained as a hydrochloride salt.

Example 42:N1-((trans)-2-(4-(1H-indazol-6-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine

¹HNMR (400 MHz, DMSO-d6-D₂O Exchange) δ: 8.11 (s, 1H), 7.86 (d, J=8 Hz,1H), 7.75 (s, 1H), 7.69 (d, J=8 Hz, 2H), 7.42 (d, J=8 Hz, 1H), 7.31 (d,J=8 Hz, 2H), 3.42 (brs, 1H), 3.36-3.20 (m, 1H), 3.10-2.98 (m, 1H),2.24-2.15 (m, 1H), 2.10-2.00 (m, 1H), 1.90 (brs, 2H), 1.81 (brs, 2H),1.63-1.35 (m, 4H); Mass (M+H): 347.2.

This compound was obtained as a hydrochloride salt.

Example 43:N1-((trans)-2-(4-(1H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine

¹HNMR (400 MHz, CD₃OD) δ: 8.24-8.15 (m, 1H), 7.80 (d, J=7.6 Hz, 2H),7.43-7.37 (m, 2H), 7.09-7.02 (m, 1H), 3.58-3.50 (m, 1H), 3.46-3.40 (m,1H), 3.22-3.08 (m, 1H), 2.77-2.59 (m, 1H), 2.40-2.29 (m, 1H), 2.24-2.15(m, 1H), 2.13-1.93 (m, 4H), 1.80-1.48 (m, 4H); Mass (M+H): 297.32. Thiscompound was obtained as a hydrochloride salt.

Example 44:3-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)thiophen-2-yl)phenol

¹HNMR (400 MHz, D₂O) δ: 7.32-7.21 (m, 2H), 7.20 (d, J=8 Hz, 1H), 7.11(s, 1H), 6.89-6.88 (m, 1H), 6.84 (d, J=7.6 Hz, 1H), 3.42-3.38 (m, 1H),3.28-3.18 (m, 1H), 3.03-2.98 (m, 1H), 2.74-2.68 (m, 1H), 2.38-2.30 (m,2H), 2.11-2.04 (m, 3H), 2.00-1.78 (m, 2H), 1.61-1.42 (m, 5H); Mass(M+H): 329.13. This compound was obtained as a hydrochloride salt.

Example 45:3-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)thiazol-2-yl)phenol

¹HNMR (400 MHz, DMSO d6) δ: 9.79 (brs, 1H), 9.70 (brs, 1H), 8.10 (brs,2H), 7.72 (s, 1H), 7.30 (s, 2H), 6.86 (s, 1H), 3.40-3.19 (m, 2H),3.18-2.95 (m, 2H), 2.85 (brs, 1H), 2.22-2.19 (m, 1H), 2.08-1.62 (m, 5H),1.58-1.38 (m, 3H); Mass (M+H): 330.2. This compound was obtained ashydrochloride salt.

Example 46:3-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)pyridin-2-yl)-5-methoxybenzonitrile

Step 1:

AcOH (12.9 mg, 0.215 mmol) was added to a solution of3-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-5-methoxybenzonitrile(Intermediate BT, 65 mg, 0.245 mmol) and tert-butyl4-oxocyclohexylcarbamate (45.9 mg, 0.215 mmol) in DCE (2 mL) and stirredat RT for 15 min., then sodium triacetoxy borohydride (82 mg, 0.387mmol) was added at 0° C. and stirred at RT for 5 h. After completion,the solvent was evaporated. The crude residue was taken up in water (10mL), basified with NaHCO₃ (10 mL), and extracted with DCM (2×10 mL). Thecombined extracts were washed with water (10 mL), brine (10 mL), driedover anhydrous Na₂SO₄, filtered and evaporated to afford tert-butyl(4-(((trans)-2-(6-(3-cyano-5-methoxyphenyl)pyridin-3-yl)cyclopropyl)amino)cyclohexyl)carbamate(110 mg). The crude product was used in the next step without furtherpurification.

Step 2:

HCl in dioxane (1 mL) was added to a solution of tert-butyl(4-(((trans)-2-(6-(3-cyano-5-methoxyphenyl)pyridin-3-yl)cyclopropyl)amino)cyclohexyl)carbamate(110 mg, 0.238 mmol) in dioxane (2 mL) at 10° C. and stirred at RT for16 h. After completion, the solvent was evaporated. The residue wastriturated with Et₂O, filtered off and dried to afford3-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)pyridin-2-yl)-5-methoxybenzonitrileas a hydrochloride salt (20 mg), an orange solid.

¹HNMR (400 MHz, CD₃OD) δ: 8.70 (s, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.96 (d,J=7.2 Hz, 1H), 7.93-7.88 (m, 1H), 7.85-7.80 (m, 1H), 7.46 (s, 1H), 3.94(s, 3H), 3.26-3.16 (m, 1H), 2.77-2.68 (m, 1H), 2.42-2.25 (m, 1H),2.24-2.10 (m, 1H), 2.08-1.90 (m, 3H), 1.89-1.80 (m, 1H), 1.78-1.27 (m,6H); Mass (M+H): 363.30

The following compound was synthesized according to the general methodsdisclosed under the General Synthetic Route Description Section and inparticular by following the method described in example 46 and utilizingthe respective intermediates.

Example 47:5-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)pyridin-2-yl)-2-methylphenol

¹HNMR (400 MHz, CD₃OD) δ: 8.74 (s, 1H), 8.33 (d, J=8.4 Hz, 1H), 8.17 (d,J=8.4 Hz, 1H), 7.35 (d, J=7.6 Hz, 1H), 7.34-7.25 (m, 2H), 3.50-3.42 (m,1H), 3.38-3.32 (m, 1H), 3.24-3.10 (m, 1H), 2.90-2.82 (m, 1H), 2.43-2.31(m, 2H), 2.28 (s, 3H), 2.23-2.12 (m, 2H), 1.84-1.78 (m, 1H), 1.76-1.50(m, 5H); Mass (M+H): 338.32. This compound was obtained as hydrochloridesalt.

Example 48:N-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-6-methoxy-[1,1′-biphenyl]-3-yl)methanesulfonamide

¹HNMR (400 MHz, CD₃OD) δ: 7.45 (d, J=8 Hz, 2H), 7.27-7.19 (m, 4H),7.10-7.02 (m, 1H), 3.78 (s, 3H), 3.08-3.00 (m, 1H), 2.91 (s, 3H),2.55-2.47 (m, 1H), 2.40-2.30 (m, 2H), 2.24-2.14 (m, 2H), 2.05-1.93 (m,2H), 1.66-1.46 (m, 6H); Mass (M+H): 430.22. This compound was obtainedas hydrochloride salt.

Example 49:N-(3-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)thiazol-2-yl)phenyl)-2-cyanobenzenesulfonamide

Step 1:

A solution of tert-butyl((trans)-2-(2-bromothiazol-5-yl)cyclopropyl)(4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate(Intermediate BQ, 1.25 g, 2.42 mmol), 3-amino phenyl boronic acid (364mg, 2.66 mmol) and K₂CO₃ (1 g, 7.26 mmol) in ACN—H₂O (4:1) (12 mL) wasdegassed for 30 minutes. Pd(PPh₃)₄ (27.9 mg, 0.024 mmol) was added, andthe mixture was stirred at reflux temperature for 16 h. Aftercompletion, the reaction mixture was poured into water and extractedwith EtOAc (2×50 mL). The combined extracts were washed with water (50mL), brine (50 mL), dried over anhydrous Na₂SO₄, filtered andevaporated. The crude was purified by column chromatography (SiO₂,EtOAc/petroleum ether 3:7) to afford tert-butyl((trans)-2-(2-(3-aminophenyl)thiazol-5-yl)cyclopropyl)(4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate(950 mg) as yellow gummy liquid.

Step 2:

2-cyanobenzene-1-sulfonyl chloride (361 mg, 1.799 mmol) was added to asolution of tert-butyl((trans)-2-(2-(3-aminophenyl)thiazol-5-yl)cyclopropyl)(4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate (950 mg, 1.799 mmol) in pyridine (5 mL) at 0°C. and stirred at RT for 5 h. After completion, the reaction mixture waspoured into water and extracted with EtOAc (2×25 mL). The combinedextracts were washed with water (2×25 mL), brine, dried over anhydrousNa₂SO₄, filtered and evaporated. The crude was purified by preparativeHPLC to afford tert-butyl(4-((tert-butoxycarbonyl)amino)cyclohexyl)((trans)-2-(2-(3-(2-cyanophenylsulfonamido)phenyl)thiazol-5-yl)cyclopropyl)carbamate(240 mg) as a white solid.

Step 3:

HCl in dioxane (1.2 mL) was added to a solution of tert-butyl(4-((tert-butoxycarbonyl)amino)cyclohexyl)((trans)-2-(2-(3-(2-cyanophenylsulfonamido)phenyl)thiazol-5-yl)cyclopropyl)carbamate (240 mg, 0.34 mmol) in dioxane (2.4mL) at 10° C. and stirred at RT for 16 h. After completion, the solventwas evaporated and the residue was triturated with Et₂O, filtered offand dried to affordN-(3-(5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)thiazol-2-yl)phenyl)-2-cyanobenzenesulfonamideas a hydrochloride salt (110 mg), a light brown solid.

¹HNMR (400 MHz, DMSO d6) δ: 11.11 (s, 1H), 9.81-9.71 (m, 2H), 8.24-8.08(brs, 2H), 8.08 (dd, J=7.6 and 4.8 Hz, 2H), 7.93 (t, J=8 Hz, 1H), 7.83(t, J=7.2 Hz, 1H), 7.73 (s, 1H), 7.66 (s, 1H). 7.56 (d, J=7.2 Hz, 1H),7.38 (t, J=8 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 3.4-3.18 (m, 2H), 3.05-2.85(m, 2H), 2.2 (m, 1H), 2.1-1.8 (m, 4H), 1.75 (brd, 2H), 1.42 (m, 3H);Mass (M+H): 494.1

The following compound was synthesized according to the general methodsdisclosed under the General Synthetic Route Description Section and inparticular by following the method described in example 49 and utilizingthe respective intermediates or commercially available reagents.

Example 50:N-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)-2-cyanobenzenesulfonamide

¹HNMR (400 MHz, DMSO-d6-D₂O Exchange) δ: 8.11 (d, J=8 Hz, 1H), 8.06 (d,J=8 Hz, 1H), 7.93 (t, J=8 Hz, 1H), 7.83 (t, J=8 Hz, 1H), 7.72-7.60 (m,1H), 7.48 (d, J=8 Hz, 2H), 7.40-7.31 (m, 2H), 7.30-7.24 (m, 2H),7.07-7.01 (m, 1H), 3.39 (brs, 1H), 3.35-3.18 (m, 1H), 3.08-2.94 (m, 2H),2.15 (brs, 1H), 2.10-2.00 (m, 1H), 1.88 (brs, 2H), 1.80 (brs, 2H),1.62-1.35 (m, 4H); Mass (M+H): 487.27. This compound was obtained ashydrochloride salt.

Example 51: 6-amino N-(4′((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)pyridine-3-sulfonamide

Step 1:

6-nitropyridine-3-sulfonyl chloride (223 mg, 1 mmol) was added to asolution of tert-butyl((trans)-2-(3′-amino-[1,1′-biphenyl]-4-yl)cyclopropyl)(4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate (Intermediate BR, 500 mg, 0.95 mmol) in pyridine(10 mL) at 0° C. and stirred at RT for 16 h. After completion, thereaction mixture was poured into water (25 mL) and extracted with EtOAc(2×25 mL). The combined extracts were washed with water (3×25 mL), brine(25 mL), dried over anhydrous Na₂SO₄, filtered and evaporated to affordtert-butyl(4-((tert-butoxycarbonyl)amino)cyclohexyl)((trans)-2-(3′-(6-nitropyridine-3-sulfonamido)-[1,1′-biphenyl]-4-yl)cyclopropyl)carbamate(580 mg). The crude product was used in the next step without furtherpurification.

Step 2:

Ammonium chloride (217 mg, 4.1 mmol) was added to a solution oftert-butyl(4-((tert-butoxycarbonyl)amino)cyclohexyl)((trans)-2-(3′-(6-nitropyridine-3-sulfonamido)-[1,1′-biphenyl]-4-yl)cyclopropyl)carbamate(580 mg, 0.82 mmol) in EtOH (12 mL) followed by iron powder (229 mg, 4.1mmol) and the reaction mixture was stirred at reflux temperature for 4h. After completion, the reaction mixture was filtered through a pad ofcelite, the filtrate was concentrated and the residue taken up in water(25 mL) and extracted with EtOAc (2×25 mL). The combined extracts werewashed with water (25 mL), brine (25 mL), dried over anhydrous Na₂SO₄,filtered and evaporated. The crude was purified by preparative HPLC toafford tert-butyl((trans)-2-(3′-(6-aminopyridine-3-sulfonamido)-[1,1′-biphenyl]-4-yl)cyclopropyl)(4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate(190 mg) as an off white solid.

Step 3:

HCl in dioxane (1 mL) was added dropwise to a solution of tert-butyl((trans)-2-(3′-(6-aminopyridine-3-sulfonamido)-[1,1′-biphenyl]-4-yl)cyclopropyl)(4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate (90 mg, 0.13 mmol) in dioxane (2 mL) at 10°C. and stirred at RT for 16 h. After completion, the solvent wasevaporated. The residue was triturated with Et₂O, filtered off and driedto render6-amino-N-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)pyridine-3-sulfonamideas a hydrochloride salt (60 mg) an off white solid.

¹HNMR (400 MHz, DMSO-d6-D₂O Exchange) δ: 8.24 (s, 1H), 7.72 (dd, J=8 Hz,2.5 Hz, 1H), 7.50 (d, J=8 Hz, 2H), 7.38-7.32 (m, 3H), 7.28 (d, J=8 Hz,1H), 7.10-7.05 (m, 1H), 6.57 (d, J=8 Hz, 2H), 3.30-3.19 (m, 1H),3.05-2.98 (m, 2H), 2.54-2.46 (m, 1H), 2.23-2.13 (m, 2H), 2.10-2.00 (m,2H), 1.59-1.36 (m, 6H); Mass (M+H): 478.06

Example 52:N-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)piperazine-1-sulfonamide

This compound was synthesized following the same procedure as describedin example 51 using tert-butyl4-(chlorosulfonyl)piperazine-1-carboxylate in Step 1 and omitting Step2. Final deprotection (Boc removal, Step 3) afforded 80 mg of the titlecompound as a hydrochloride salt, a white solid.

¹HNMR (400 MHz, DMSO-d6-D₂O Exchange) δ: 7.57 (d, J=8 Hz, 2H), 7.50-7.38(m, 3H), 7.35-7.25 (m, 2H), 7.24 (d, J=8 Hz, 1H), 3.37 (brs, 4H),3.36-3.20 (m, 2H), 3.37 (brs, 4H), 3.11 (brs, 3H), 3.05-2.96 (m, 2H),2.23-2.15 (m, 1H), 2.10-2.0 (m, 1H), 1.90 (brs, 2H), 1.81 (brs, 2H),1.63-1.35 (m, 4H); Mass (M+H): 470.33

Example 53:N1-((trans)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1,4-diamine

Step 1:

Tert-butyl 4-oxocyclohexylcarbamate (493 mg, 2.31 mmol) was added to asolution of (trans)-2-fluoro-2-phenylcyclopropanamine (Intermediate BJ,350 mg, 2.31 mmol) in DCE (7 mL). The mixture was stirred at RT for 10min and then cooled to 0° C. Sodium triacetoxy borohydride (978 mg, 4.62mmol) was added and stirring was continued at RT for 15 min. Aftercompletion the reaction mixture was poured into ice water and extractedwith DCM (2×25 mL). The combined extracts were washed with water (10mL), brine (10 mL) and dried over anhydrous Na₂SO₄. The filtrate wasused in the next step without evaporation.

HCl in Dioxane (1.6 mL) was added the solution of tert-butyl(4-(((trans)-2-fluoro-2-phenylcyclopropyl)amino)cyclohexyl)carbamate inDCM (3.2 mL) and stirred at RT for 16 h. After completion, the solventwas evaporated, and the crude residue was triturated with diethyl ether(10 mL) and hexane (10 mL) to affordN1-((trans)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1,4-diamine ashydrochloride salt (300 mg) as a yellow solid.

Step 2:

2N NaOH solution (5.8 mL) and (Boc)₂O (0.54 mL, 2.26 mmol) was added toa solution ofN1-((trans)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1,4-diamine (290mg, 0.906 mmol) in 1,4 dioxane (10 vols) at 10° C. and stirred at roomtemp for 4 h. After completion, the reaction mixture was diluted withwater (10 mL) and extracted with EtOAc (2×15 mL). The combined extractswere washed with water (10 mL), brine (10 mL), dried over anhydrousNa₂SO₄, filtered and evaporated. The crude was purified by preparativeHPLC to afford tert-butyl(4-((tert-butoxycarbonyl)amino)cyclohexyl)((trans)-2-fluoro-2-phenylcyclopropyl)carbamate(140 mg) as a white solid.

Step 3:

HCl in dioxane (0.7 ml) was added to a solution of tert-butyl(4-((tert-butoxycarbonyl)amino)cyclohexyl)((trans)-2-fluoro-2-phenylcyclopropyl)carbamate(140 mg, 0.312 mmol) in dioxane (1.4 mL) at 0° C. and stirred at RT for6 h. After completion, the solvent was evaporated and the residue wastriturated with diethyl ether (5 mL) followed by n-pentane (5 mL) to getN1-((trans)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1,4-diamine as ahydrochloride salt (80 mg), an off white solid.

¹HNMR (400 MHz, D₂O) δ: 7.49 (s, 2H), 7.42 (s, 3H), 3.60-3.43 (m, 2H),3.22-3.12 (m, 2H), 2.33-2.18 (m, 3H), 1.98-1.91 (m, 3H), 1.68-1.45 (m,3H), Mass (M+H): 249.17

Example 54:N1-((cis)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1,4-diamine

This compound was synthesized following the same procedure as describedin example 53 starting from (cis)-2-fluoro-2-phenylcyclopropanamine(Intermediate BI), affording 80 mg as a hydrochloride salt, an off whitesolid.

¹HNMR (400 MHz, D₂O) δ: 7.79 (s, 2H), 7.62 (s, 3H), 3.69-3.53 (m, 2H),3.4-3.18 (m, 2H), 2.39 (s, 1H), 2.28-2.08 (m, 3H), 2.02-1.81 (m, 4H),1.68-1.45 (m, 3H), Mass (M+H): 249.17

Example 55:N1-((trans)-2-(4-((3-(piperazin-1-yl)benzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine

Step 1:

K₂CO₃ (1.1 g, 8.0 mmol) was added to a solution of tert-butyl((trans)-2-(4-hydroxyphenyl)cyclopropyl)carbamate (Intermediate BL, 1 g,4.0 mmol) and 1-bromo-3-(bromomethyl)benzene (997 mg, 4.0 mmol) in DMF(10 mL) at 0° C. and stirred at RT for 18 h. After completion, thereaction mixture was poured into ice water (20 mL) and extracted withethyl acetate (2×20 mL). The combined extracts were washed with water(20 mL), brine (20 mL), dried over anhydrous Na₂SO₄, filtered andevaporated. The crude product was purified by column chromatography(SiO₂, EtOAc/petroleum ether 2:8) to afford tert-butyl((trans)-2-(4-((3-bromobenzyl)oxy)phenyl)cyclopropyl) carbamate (1.2 g)as an off white solid.

Step 2:

HCl in dioxane (10 mL) was added dropwise to a solution of tert-butyl((trans)-2-(4-((3-bromobenzyl)oxy)phenyl)cyclopropyl)carbamate (1.2 g,2.8 mmol) in dioxane (5 mL) at 15° C. and stirred at RT for 2 h. Aftercompletion, the solvent was evaporated. The residue was taken up inwater (15 mL), basified with NaHCO₃ solution (5 mL) and extracted withEtOAc (2×20 mL). The combined extracts were washed with water (20 mL),brine (20 mL), dried over anhydrous Na₂SO₄, filtered and evaporated toafford (trans)-2-(4-((3-bromobenzyl)oxy)phenyl)cyclopropanamine (800mg). The crude was used in the next step without further purification.

Step 3:

Acetic acid (0.17 mL, 2.515 mmol) was added to a solution of(trans)-2-(4-((3-bromobenzyl)oxy)phenyl)cyclopropanamine (800 mg, 2.51mmol) and tert-butyl 4-oxocyclohexylcarbamate (537 mg, 2.515 mmol) inDCE (20 mL). At 0° C., sodium triacetoxy borohydride (960 mg, 4.52 mmol)was added, and the mixture was stirred at RT for 4 h. After completion,the reaction mixture was diluted with DCM (20 mL), washed with aq.NaHCO₃ solution, followed by water (10 mL), brine (10 mL). The organicphase was dried over anhydrous Na₂SO₄, filtered and evaporated. Thecrude product was purified by column chromatography (SiO₂,EtOAc/petroleum ether 6:4) to afford tert-butyl(4-(((trans)-2-(4-((3-bromobenzyl)oxy)phenyl)cyclopropyl)amino)cyclohexyl)carbamate (900 mg).

Step 4:

NaOH (310 mg, 7.76 mmol) was added to a solution of tert-butyl(4-(((trans)-2-(4-((3-bromobenzyl)oxy)phenyl)cyclopropyl)amino)cyclohexyl)carbamate(1.0 g, 1.94 mmol) in 1,4-dioxane/water (4:1) at 10° C. Subsequently,Boc₂O (830 mg, 3.88 mmol) was added, and the mixture was stirred at RTfor 18 h. After completion, the reaction mixture was poured into icewater (20 mL) and extracted with ethyl acetate (2×20 mL). The combinedextracts were washed with water (20 mL), brine (20 mL), dried overanhydrous Na₂SO₄, filtered and evaporated. The crude product waspurified by column chromatography (SiO₂, EtOAc/petroleum ether 3:7) toafford tert-butyl((trans)-2-(4-((3-bromobenzyl)oxy)phenyl)cyclopropyl)(4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate (600 mg).

Step 5:

NaO^(t)Bu (141 mg, 1.46 mmol) was added to a solution of tert-butyl((trans)-2-(4-((3-bromobenzyl)oxy)phenyl)cyclopropyl)(4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate(600 mg, 0.975 mmol) and tert-butyl piperazine-1-carboxylate (363 mg,1.95 mmol) in dioxane (15 mL) at RT which was then degassed with argonfor 15 min. Pd₂(dba)₃ (44.6 mg, 0.0487 mmol) was added followed byxantphos (169 mg, 0.292 mmol), and degassing was repeated for 15 min.The reaction mixture was stirred at reflux temperature for 18 h. Aftercompletion, the mixture was filtered through a pad of celite, and thefiltrate was concentrated. The residue was taken up in water (20 mL) andextracted with ethyl acetate (2×20 mL). The combined extracts werewashed with water (20 mL), brine (20 mL), dried over anhydrous Na₂SO₄,filtered and evaporated. The crude product was purified by columnchromatography (neutral alumina, EtOAc/petroleum ether 2:8) to affordtert-butyl4-(3-((4-((trans)-2-((tert-butoxycarbonyl)(4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)cyclopropyl)phenoxy)methyl)phenyl)piperazine-1-carboxylate (260 mg) as a white solid.

Step 6:

HCl in dioxane (3 mL) was added to a solution of tert-butyl4-(3-((4-((trans)-2-((tert-butoxycarbonyl)(4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)cyclopropyl)phenoxy)methyl)phenyl)piperazine-1-carboxylate (150 mg, 0.208 mmol) in 1,4-dioxane (2 mL) at 10° C. and stirred at RT for 6 h. After completion,the solvent was evaporated and the residue was triturated with EtOAc (4mL), followed by n-hexane (2 mL) to affordN1-((trans)-2-(4-((3-(piperazin-1-yl)benzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamineas hydrochloride salt (80 mg), a pale yellow solid.

¹HNMR (400 MHz, D₂O) δ: 7.40 (t, J=8 Hz, 1H), 7.19 (s, 1H), 7.18-7.07(m, 4H), 7.01 (d, J=8 Hz, 2H), 5.11 (s, 2H), 3.6-3.3 (m, 9H), 3.28-3.18(m, 1H), 3.95-3.84 (m, 1H), 2.50-2.39 (m, 1H), 2.32-2.24 (m, 1H),2.19-2.11 (m, 1H), 2.09-1.99 (m, 1H), 1.98-1.77 (m, 3H), 1.62-1.33 (m,4H); Mass (M+H): 421.28

The following compounds were synthesized according to the generalmethods disclosed under the General Synthetic Route Description Sectionand in particular by following the method described in example 55,omitting Steps 4 and 5, and utilizing the respective intermediates orcommercially available reagents.

Example 56:N1-((trans)-2-(4-(pyridin-3-ylmethoxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine

¹HNMR (400 MHz, DMSO-d6-D₂O Exchange) δ: 8.79 (s, 1H), 8.68 (s, 1H),8.31-8.24 (m, 1H), 7.83-75 (m, 1H), 7.20-7.10 (m, 2H), 7.01 (d, J=8.4Hz, 2H), 5.23 (s, 2H), 3.42-3.17 (m, 2H), 3.08-2.95 (m, 1H), 2.94-2.83(m, 1H), 2.48-2.35 (m, 1H), 2.22-2.10 (m, 1H), 2.09-1.98 (m, 1H),1.97-1.72 (m, 3H), 1.55-1.38 (m, 3H), 1.37-1.25 (m, 1H); Mass (M+H):338.19. This compound was obtained as hydrochloride salt.

Example 57:N1-((trans)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine

¹HNMR (400 MHz, DMSO d6) δ: 9.55 (brd, 2H), 8.1 (brs, 3H), 7.58 (t, 1H),7.62 (d, 1H), 7.28 (m, 2H), 7.18 (d, 2H), 6.98 (d, 2H), 5.1 (s, 2H),3.25-3.15 (m, 2H), 2.88-2.81 (m, 2H), 2.45 (brs, 1H), 2.15 (brs, 1H),2.05-1.7 (m, 5H), 1.6-1.3 (m, 3H), 1.25 (d, 1H); Mass (M+H): 355.25.This compound was obtained as hydrochloride salt.

Example 58:N1-((trans)-2-(6-((3-methylbenzyl)amino)pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine

Step 1:

A solution of tert-butyl((trans)-2-(6-bromopyridin-3-yl)cyclopropyl)(4-((tert-butoxycarbonyl)amino)cyclohexyl)carbamate(Intermediate BP, 300 mg, 0.58 mmol), m-tolylmethanamine (78 mg, 0.64mmol), sodium tert-butoxide (83 mg, 0.87 mmol) and BINAP (108 mg, 0.17mmol) in 1,4-dioxane (6 mL) was degassed for 10 min.Tris(dibenzylideneacetone) dipalladium(0) (26 mg, 0.029 mmol) was added,and the reaction mixture was stirred at 100° C. for 16 h. Aftercompletion, the reaction mixture was poured in ice cold water (15 mL)and extracted with EtOAc (2×10 mL). The combined extracts were washedwith water (10 mL), brine (10 mL), dried over anhydrous Na₂SO₄, filteredand evaporated. The crude residue was purified by column chromatography(SiO₂) using EtOAc:petroleum ether (3:7) to afford tert-butyl(4-((tert-butoxycarbonyl)amino)cyclohexyl)((trans)-2-(6-((3-methylbenzyl)amino)pyridin-3-yl)cyclopropyl)carbamate (100 mg) as a white solid.

Step 2:

HCl in 1,4-dioxane (1 mL) was added to a solution of tert-butyl(4-((tert-butoxycarbonyl)amino)cyclohexyl)((trans)-2-(6-((3-methylbenzyl)amino)pyridin-3-yl)cyclopropyl)carbamate (100 mg, 0.181 mmol) in dioxane (2 mL) at 10° C.,and the reaction mixture was stirred at RT for 16 h. After completion,the solvent was evaporated. The solid residue was triturated with Et₂Oand hexane to affordN1-((trans)-2-(6-((3-methylbenzyl)amino)pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamineas hydrochloride salt (60 mg), a brown solid.

¹HNMR (400 MHz, D₂O) δ: 7.68 (d, J=9.6 Hz, 1H), 7.63 (s, 1H), 7.30 (t,J=8 Hz, 1H), 7.24-7.16 (m, 3H), 6.99 (d, J=9.4 Hz, 2H), 4.56 (s, 2H),3.58-3.47 (m, 1H), 3.42-3.31 (m, 1H), 3.27-3.17 (m, 1H), 3.05-2.95 (m,1H), 2.52-2.41 (m, 1H), 2.30 (s, 3H), 2.27-2.23 (m, 1H), 2.20-2.12 (m,2H), 2.00-1.80 (m, 2H), 1.64-1.39 (m, 4H); Mass (M+H): 351.41

Example 59:3-((5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)pyridin-2-yl)amino)benzonitrile

Step 1:

A solution of tert-butyl(trans)-2-(6-bromopyridin-3-yl)cyclopropylcarbamate (Intermediate M, 250mg, 0.798 mmol), 3-aminobenzonitrile (113 mg, 0.957 mmol) and sodiumtert-butoxide (115 mg, 1.197 mmol) in 1,4-dioxane (5 mL) was degassedfor 30 min., then tris(dibenzylideneacetone)dipalladium(0) (36 mg, 0.039mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos)(138 mg, 0.238 mmol) was added and the reaction was heated for 1 h at80° C. After completion, the solvent was evaporated, the residue wastaken in ice water (10 mL) and extracted with EtOAc (2×20 mL). Thecombined extracts were washed with water (10 mL), brine (10 mL), driedover anhydrous Na₂SO₄, filtered and evaporated. The crude residue waspurified by column chromatography (SiO₂) using EtOAc:petroleum ether(2:8) to give tert-butyl((trans)-2-(6-((3-cyanophenyl)amino)pyridin-3-yl)cyclopropyl)carbamate(100 mg) as a yellow solid.

Step 2:

HCl in 1, 4 dioxane (1 ml) was added to a solution of tert-butyl((trans)-2-(6-((3-cyanophenyl)amino)pyridin-3-yl)cyclopropyl)carbamate(100 mg, 0.285 mmol) in 1, 4-dioxane (1 mL) at 0° C. and stirred at RTfor 4 h. After completion, the solvent was evaporated and the residuewas triturated with diethyl ether (5 mL) followed by n-pentane (5 mL) togive 3-((5-((trans)-2-aminocyclopropyl)pyridin-2-yl)amino)benzonitrileas hydrochloride salt (80 mg), a pale yellow solid.

Step 3:

AcOH (11.46 mg, 0.191 mmol) was added to a solution of3-((5-((trans)-2-aminocyclopropyl)pyridin-2-yl)amino)benzonitrile (55mg, 0.191 mmol) and tert-butyl 4-oxocyclohexylcarbamate (40.68 mg, 0.191mmol) in DCE (1 mL) and stirred at RT for 15 min., then sodiumtriacetoxy borohydride (72.8 mg, 0.343 mmol) was added at 0° C. andstirred at RT for 5 h. After completion, solvent was evaporated. Thecrude residue was taken up in water (10 mL), basified with NaHCO₃ (10mL), and extracted with DCM (2×10 mL). The combined extracts were washedwith water (10 mL), brine (10 mL), dried over anhydrous Na₂SO₄, filteredand evaporated to afford tert-butyl(4-(((trans)-2-(6-((3-cyanophenyl)amino)pyridin-3-yl)cyclopropyl)amino)carbamate(75 mg) as light yellow oil. The crude product was used in the next stepwithout further purification.

Step 4:

HCl in 1,4-dioxane (1 mL) was added to a solution of tert-butyl(4-(((trans)-2-(6-((3-cyanophenyl)amino)pyridin-3-yl)cyclopropyl)amino)cyclohexyl)carbamate(75 mg, 0.167 mmol) in 1,4-dioxane (2 mL) at 10° C. and stirred at RTfor 16 h. After completion, the solvent was evaporated. The solid wastriturated with Et₂O and dried to afford crude product. The crude waspurified by Preparative HPLC to afford3-((5-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)pyridin-2-yl)amino)benzonitrileas a hydrochloride salt (28 mg), an off white sticky solid.

¹HNMR (400 MHz, DMSO-d6-D₂O Exchange) δ: 8.35 (s, 1H), 8.15 (s, 1H),7.78 (d, J=8 Hz, 1H), 7.54-7.42 (m, 2H), 7.31 (d, J=8 Hz, 1H), 6.85 (d,J=8.8 Hz, 1H), 3.45-3.17 (m, 2H), 3.08-2.93 (m, 2H), 2.44-2.34 (m, 1H),2.22-2.10 (m, 1H), 2.09-1.98 (m, 1H), 1.97-1.70 (m, 3H), 1.55-1.32 (m,4H); Mass (M+H): 348.20

The following compounds can be synthesized following the general methodsdisclosed under the General Synthetic Route Description Section,including the methodologies described in Schemes 1, 2, 3, 4, 5, 6, 7 or8 and the examples above.

Example 60:N1-((trans)-2-(4′-chloro-[1,1′-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamineNH₂

Example 61:N1-((trans)-2-(3′-chloro-[1,1′-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine

Example 62:4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-ol

Example 63:N-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)[1,1′-biphenyl]-3-yl)methanesulfonamide

Example 64:N1-((trans)-2-(4-((3-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine

Example 65:N1-((trans)-2-(4-((4-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine

Example 66:N1-methyl-N4-((trans)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)cyclohexane-1,4-diamine

Example 67:N1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)-N4-methylcyclohexane-1,4-diamine

Example 68:N1-((trans)-2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)cyclobutane-1,3-diamine

Example 69:N1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)cyclobutane-1,3-diamine

Example 70: N1-((trans)-2(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)cyclopropyl)-2,3-dihydro-1H-indene-1,3-diamine

Example 71:N1-((trans)-2-(4-(benzyloxy)phenyl)cyclopropyl)-2,3-dihydro-1H-indene-1,3-diamine

Example 72:N1-((1S,2S)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1,4-diamine

Example 73:N1-((1R,2R)-2-fluoro-2-phenylcyclopropyl)cyclohexane-1,4-diamine

Example 74:N1-((trans)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine

Example 75: N1-((trans)-2-(o-tolyl)cyclopropyl)cyclohexane-1,4-diamine

Example 76:N1-((trans)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)cyclohexane-1,4-diamine

Example 77:N1-((trans)-2-(4-methoxyphenyl)cyclopropyl)cyclohexane-1,4-diamine

Example 79:N1-((trans)-2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1,4-diamine

Example 80:N1-((trans)-2-methyl-2-phenylcyclopropyl)cyclohexane-1,4-diamine

Example 81:(cis)-N1-((1S,2R)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine

Example 82:(trans)-N1-((R,2S)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine

Example 83:(cis)-N1-((1R,2S)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine

Example 84:(trans)-N1-((1S,2R)-2-(pyridin-3-yl)cyclopropyl)cyclohexane-1,4-diamine

Example 85:(cis)-N1-((1S,2R)-2-phenylcyclopropyl)cyclobutane-1,3-diamine

Example 86:(trans)-N1-((1R,2S)-2-phenylcyclopropyl)cyclobutane-1,3-diamine

Example 87:(cis)-N1-((1R,2S)-2-phenylcyclopropyl)cyclobutane-1,3-diamine

Example 88:(trans)-N1-((1S,2R)-2-phenylcyclopropyl)cyclobutane-1,3-diamine

Example 89:(cis)-N1-((1S,2R)-2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1,4-diamine

Example 90:(trans)-N1-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1,4-diamine

Example 91:(cis)-N1-((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1,4-diamine

Example 92:(trans)-N1-((1S,2R)-2-(3,4-difluorophenyl)cyclopropyl)cyclohexane-1,4-diamine

Example 93:(cis)-N1-((1S,2R)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine

Example 94:(trans)-N1-((1R,2S)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine

Example 95:(cis)-N1-((1R,2S)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine

Example 96:(trans)-N1-((1S,2R)-2-(naphthalen-2-yl)cyclopropyl)cyclohexane-1,4-diamine

Example 97:(cis)-N1-((1S,2R)-2-(4-(1H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine

Example 98:(trans)-N1-((1R,2S)-2-(4-(1H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine

Example 99:(cis)-N1-((1R,2S)-2-(4-(1H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine

Example 100:(trans)-N1-((1S,2R)-2-(4-(1H-pyrazol-5-yl)phenyl)cyclopropyl)cyclohexane-1,4-diamine

Example 101:N-(4′-((1R,2S)-2-(((cis)-4-aminocyclohexyl)amino)cyclopropyl-[1,1′-biphenyl]-3-yl)piperazine-1-sulfonamide

Example 102:N-(4′-((1S,2R)-2-(((trans)-4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)piperazine-1-sulfonamide

Example 103:N-(4′-((1S,2R)-2-(((cis)-4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)piperazine-1-sulfonamide

Example 104:N-(4′-((1R,2S)-2-(((trans)-4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)piperazine-1-sulfonamide

Example 105:(cis)-N1-((1S,2R)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine

Example 106:(trans)-N1-((1R,2S)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine

Example 107:(cis)-N1-((1R,2S)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine

Example 108:(trans)-N1-((1S,2R)-2-(4-((2-fluorobenzyl)oxy)phenyl)cyclopropyl)cyclohexane-1,4-diamine

Biological Assays

Example 109: Biological Assays—Inhibition of LSD1

The compounds of the invention can be tested for their ability toinhibit LSD1. The ability of the compounds of the invention to inhibitLSD1 can be tested as follows. Human recombinant LSD1 protein waspurchased from BPS Bioscience Inc (catalog reference number 50100: humanrecombinant LSD1, GenBank accession no. NM_015013, amino acids 158-endwith N-terminal GST tag, MW: 103 kDa). In order to monitor LSD1enzymatic activity and/or its inhibition rate by our inhibitor(s) ofinterest, di-methylated H3-K4 peptide (Anaspec) was chosen as asubstrate. The demethylase activity was estimated, under aerobicconditions, by measuring the release of H₂O₂ produced during thecatalytic process, using the Amplex® Red hydrogen peroxide/peroxidaseassay kit (Invitrogen).

Briefly, a fixed amount of LSD1 was incubated on ice for 15 minutes, inthe absence and/or in the presence of at least eight 3-fold serialdilutions of the respective inhibitor (e.g., from 0 to 75 μM, dependingon the inhibitor strength). Tranylcypromine (Biomol International) wasused as a control for inhibition. Within the experiment, eachconcentration of inhibitor was tested in duplicate. After leaving theenzyme interacting with the inhibitor, K_(M) of di-methylated H3-K4peptide was added to each reaction and the experiment was left for 30minutes at 37° C. in the dark. The enzymatic reactions were set up in a50 mM sodium phosphate, pH 7.4 buffer. At the end of the incubation,Amplex® Red reagent and horseradish peroxidase (HPR) solution were addedto the reaction according to the recommendations provided by thesupplier (Invitrogen), and left to incubate for 5 extra minutes at roomtemperature in the dark. A 1 μM H₂O₂ solution was used as a control ofthe kit efficiency. The conversion of the Amplex® Red reagent toresorufin due to the presence of H₂O₂ in the assay, was monitored byfluorescence (excitation at 540 nm, emission at 590 nm) using amicroplate reader (Infinite 200, Tecan). Arbitrary units were used tomeasure level of H₂O₂ produced in the absence and/or in the presence ofinhibitor.

The maximum demethylase activity of LSD1 was obtained in the absence ofinhibitor and corrected for background fluorescence in the absence ofLSD1. The IC50 value of each inhibitor was calculated with GraphPadPrism Software.

The results presented in Table 1 below show the results of the LSD1inhibition studies for a number of the Example compounds. In Table 2 theIC50 values for all examples tested in this assay are shown. Parnate(tranylcypromine; i.e., 2-trans phenylcyclopropylamine) was found tohave a IC50 value of 35±10 micromolar. The studies show that thecompounds of the invention have unexpectedly potent LSD1 inhibition.

Example 110: Biological Assays—Monoamine Oxidase Assays for Determiningthe Selectivity of the Compounds of the Invention for LSD1

Human recombinant monoamine oxidase proteins MAO-A and MAO-B werepurchased from Sigma Aldrich. MAOs catalyze the oxidative deamination ofprimary, secondary and tertiary amines. In order to monitor MAOenzymatic activities and/or their inhibition rate by inhibitor(s) ofinterest, a fluorescence-based (inhibitor)-screening assay was set up.3-(2-Aminophenyl)-3-oxopropanamine (kynuramine dihydrobromide, SigmaAldrich), a non fluorescent compound was chosen as a substrate.Kynuramine is a non-specific substrate for both MAO-A and MAO-Bactivities. While undergoing oxidative deamination by MAO activities,kynuramine is converted into 4-hydroxyquinoline (4-HQ), a resultingfluorescent product.

The monoamine oxidase activity was estimated by measuring the conversionof kynuramine into 4-hydroxyquinoline. Assays were conducted in 96-wellblack plates with clear bottom (Corning) in a final volume of 100 μL.The assay buffer was 100 mM HEPES, pH 7.5. Each experiment was performedin duplicate within the same experiment.

Briefly, a fixed amount of MAO (0.25 μg for MAO-A and 0.5 μg for MAO-B)was incubated on ice for 15 minutes in the reaction buffer, in theabsence and/or in the presence of at least eight 3-fold serial dilutionseach. Clorgyline and Deprenyl (Sigma Aldrich) was used as a control forspecific inhibition of MAO-A and MAO-B respectively.

After leaving the enzyme(s) interacting with the inhibitor, K_(M) ofkynuramine was added to each reaction for MAO-B and MAO-A assayrespectively, and the reaction was left for 1 hour at 37° C. in thedark. The oxidative deamination of the substrate was stopped by adding50 μL of NaOH 2N. The conversion of kynuramine to 4-hydroxyquinoline,was monitored by fluorescence (excitation at 320 nm, emission at 360 nm)using a microplate reader (Infinite 200, Tecan). Arbitrary units wereused to measure levels of fluorescence produced in the absence and/or inthe presence of inhibitor.

The maximum of oxidative deamination activity was obtained by measuringthe amount of 4-hydroxyquinoline formed from kynuramine deamination inthe absence of inhibitor and corrected for background fluorescence inthe absence of MAO enzymes. The IC50 values of each inhibitor werecalculated with GraphPad Prism Software.

The results obtained with compounds of the invention in the biologicalassays of examples 109 and 110 are shown below.

TABLE 1 Summary of Data from MAO-A, MAO-B, and LSD1 Inhibition StudiesExample No. MAO-A (Ki) MAO-B (Ki) LSD1 (Ki) 1 I I IV 2 I I III 3 I I III4 I I IV 5 I I IV 8 I II III 11 II II III 12 II II IV 13 II II III 14 IIII III 15 II II IV

The ranges for the Ki value reported in Table 1 are for MAO-A, MAO-B andLSD1: I=higher than 40 μM II=between 1 μM and 40 μM; III=between 0.1 μMand 1 μM; IV=between 0.001 μM and 0.1 μM. The term Ki value is usedherein as a designation for the IC50 value, i.e. the concentrationrequired for a half-maximal (50%) inhibition of the corresponding target(MAO-A, MAO-B, or LSD1).

Generally compounds of the invention were found to have particularly lowIC50 values for LSD1, as compared to MAO-A and MAO-B. For some of thecompounds of the Examples, IC50 values for LSD1 were lower than 0.1 μM.

The specific IC50 values obtained for the compounds disclosed in theExamples when tested in the assays of Examples 109 (LSD1 inhibition) and110 (MAO-A and B inhibition) are provided in Table 2 below:

Example MAO-A MAO-B LSD1 no. (IC50 - μM) (IC50 - μM) (IC50 - μM) 1 >10044.17 0.017 2 >100 >100 0.135 3 >100 >100 0.292 4 >100 >100 0.0335 >100 >100 0.015 6 >100 >100 0.034 7 >100 >100 0.069 8 >100 10.07 0.1189 ≈50 1.84 0.048 10 1.64 0.98 0.040 11 32.02 6.80 0.131 12 25.20 2.500.091 13 ≈100 2.45 0.402 14 ≈50 2.23 0.146 15 >100 >100 0.081 16 >100≈100 0.148 17 >100 ≈100 uM 0.062 18 >100 >100 0.045 19 >100 >100 0.06820 >100 59.09 0.034 21 5.23 1.36 0.053 22 >100 ≈100 0.066 23 >100 46.3631.070 24 >100 ≈100 5.705 25 >100 ≈100 1.330 26 ≈100 ≈100 0.05127 >100 >100 0.027 28 >100 7.56 0.037 29 >100 >100 0.036 30 >100 >1006.772 31 >100 >100 0.035 32 >100 >100 0.037 33 >50 ≈50 0.021 34 >50 ≈500.047 35 5.58 6.50 0.128 36 10.70 2.27 0.086 37 14.64 6.65 0.094 3826.78 2.41 0.053 39 26.29 10.56 0.089 40 >100 18.35 0.034 41 ≈100 ≈1000.047 42 8.93 8.48 0.027 43 >100 >100 0.022 44 18.18 2.04 0.041 45 29.463.23 0.032 46 >100 >100 0.138 47 ≈100 ≈50 0.083 48 17.48 >100 0.027 49≈100 ≈100 0.079 50 >100 ≈100 0.062 51 ≈100 ≈100 0.030 52 ≈100 65.010.019 53 ≈100 15.36 0.045 54 >100 >100 22.080 55 >100 17.13 0.033 56≈100 >50 0.094 57 13.56 3.24 0.012 58 51.70 3.62 0.042 59 >100 ≈50 0.054

As the data in the above table show, the compounds of the invention arevery potent LSD1 inhibitors, with IC50 values in many cases below 100 nMor even below 50 nM. In addition, the compounds exhibit high selectivityversus MAO-A and MAO-B, with IC50 values for LSD1 in general ≥100-foldmore potent than the corresponding IC50 values for MAO-A and MAO-B.

Example 111: Cellular Assay—Induction of Differentiation of THP-1Leukemia Cells

Acute Myeloid Leukemia (AML) is characterized by the presence ofleukemic cells with a maturation arrest that divide rapidly. With theinduction of terminal differentiation, AML cells lose the ability toproliferate and end up dying without the need of a direct cytotoxiceffect.

By analyzing the induction of CD11b membrane expression on THP-1 cellswe are assessing the ability of LSD1 inhibitors to induce terminalmonocytic differentiation of a MLL-AF9 AML cell line.

The assay was performed as follows:

THP-1 cells were established from the peripheral blood of a 1-year-oldboy with acute monocytic leukemia at relapse in 1978. They carryt(9;11)(p21;q23) leading to MLL-MLLT3 (MLL-AF9) fusion gene. This cellline can undergo monocytic differentiation upon treatment with theappropriate stimulus. THP-1 were purchased from DSMZ GmbH (DeutscheSammlung von Mikroorganismen und Zellkulturen) and cultured in RPMI 1640medium containing 10% of fetal bovine serum.

In this assay, 150, 000 THP-1 cells were seeded in 1 ml of completeculture medium in 6-well tissue culture plates. Serial dilutions of thecompounds were prepared in DMSO and then further diluted in completemedium to generate solutions of concentrations that are double of thefinal concentration at which the cells will be exposed. 1 ml of these 2×concentrated solutions was added to the cells. DMSO final content mustbe the same in all the wells and must be kept below 0.1% v/v (usually0.01-0.02% v/v), since higher DMSO content can induce differentiation ofTHP-1 cells.

Cells were kept in the presence of test compound for 96 h at a 5% CO₂atmosphere at 37° C. After this treatment period, cells were harvested,washed twice with PBS buffer and placed in a V-bottom 96-well plate.Each treated sample was split in two. One was stained with aphycoerythrin-labeled anti-CD11b antibody (clone ICRF44, purchased fromeBiosciences) and the other with the relevant phycoerythrin-labeledisotype control antibody (mouse IgG₁, purchased from eBiosciences).Samples were incubated in the dark at 4° C. for 30-60 minutes and washedthree times in PBS buffer containing 1% fetal bovine serum.

Samples were analyzed in a flow cytometer equipped with a blue laser(488 nm). Emitted fluorescence was detected and quantified with a 575/30nm filter. Percentage of CD11b positive cells, as an indicator ofmonocytic differentiation, was determined compared to isotype controlantibody stained cells. EC50 values were calculated by non-linearregression analysis.

The results obtained with compounds of the invention in this test areshown in Table 3 below.

Example No EC50 (nM) 3 13% CD11b+ cells at 100 nM 4 5.3 5 0.8 6 >200 176.3 19 2.2 22 3.6 26 9.7 33 13.9 38 20.0 39 6.6 40 2.5 42 82.4 57 2.0

These results show that compounds of the invention exhibit very potentactivity in inducing differentiation of leukemia THP-1 cells, whichindicates that these compounds are particularly useful for the treatmentor prevention of leukemias.

Previous reports of LSD1 have found that it is involved in cellproliferation and growth. Some studies have implicated LSD1 as atherapeutic target for cancer. Huang et al. (2007) PNAS 104:8023-8028found that polyamine inhibitors of LSD1 modestly cause the reexpressionof genes aberrantly silenced in cancer cells and particularly colorectalcancer (Huang et al. Clin Cancer Res. (2009) December 1; 15(23):7217-28. Epub 2009 Nov. 24. PMID: 19934284). Scoumanne et al.((2007) J. Biol. Chem. May 25; 282 (21):15471-5) found that deficiencyin LSD1 leads to a partial cell cycle arrest in G2/M and sensitizescells to growth suppression induced by DNA damage. Kahl et al. ((2006)Cancer Res. 66 (23):11341-7) found that LSD1 expression is correlatedwith prostate cancer aggressiveness. Metzger et al. ((2005) Nature, 437(7057), 436-439) reported that LSD1 modulation by siRNA and pargylineregulates androgen receptor (AR) and may have therapeutic potential incancers where AR plays a role, like prostate, testis, and brain cancers.Lee et al. ((2006) Chem. Biol. 13:563-567) reported that tranylcyprominederepresses Egr-1 gene expression in some cancer lines. A body ofevidence is accumulating that Egr-1 is a tumor suppressor gene in manycontexts (see e.g., Calogero et al. (2004) Cancer Cell International 4:1exogenous expression of EGR-1 resulted in growth arrest and eventualcell death in primary cancer cell lines; Lucerna et al. (2006) CancerResearch 66 (13), 6708-6713 show that sustained expression of Egr-1causes antiangiogeneic effects and inhibits tumor growth in some models;Ferraro et al. ((2005) J. Clin. Oncol. March 20; 23 (9):1921-6) reportedthat Egr-1 is downregulated in lung cancer patients with a higher riskof recurrence and may be more resistant to therapy. Thus, increasingEgr-1 expression via inhibition of LSD1 is a therapeutic approach forsome cancers. Recent studies have also implicated LSD1 in brain cancer(Schulte et al. (2009) Cancer Res. March 1; 69 (5):2065-71). Otherstudies have implicated LSD1 in breast cancer (Lim et al.Carcinogenesis, (2010), 31 (3): 512-20, Epub 2009 Dec. 30. [Epub aheadof print] PMID: 20042638), lung, bladder and colorectal cancers (Hayamiet al (2011), Int J Cancer, 128 (3): 574-86, PMID: 20333681) andleukemia (Binda et al (2010), J Am Chem Soc, 132 (19): 6827-33, PMID:20415477).

Thus, a body of evidence has implicated LSD1 in a number of cancers,which suggests that LSD1 is a therapeutic target for cancer. The instantinventors have discovered a class of LSD1 inhibitors that can be used totreat diseases where LSD1 is implicated as a therapeutic target likecancer. Accordingly, the (hetero)aryl cyclopropylamine compounds of theinvention can be used to treat such diseases.

Recent studies have also implicated LSD1 in viral infection andreactivation. In particular it was shown that pharmacological inhibitorsof LSD1 like parnate and siRNA knock down of LSD1 caused reduced viralinfectivity and reduced reactivation after latency (Liang et al. (2009)Nat. Med. 15 (11):1312-1317). Therefore it is believed that thecompounds of the invention can be used for treating or preventing viralinfection. Furthermore, it is believed that the compounds of theinvention can treat or prevent viral reactivation after latency.

Thus, without being bound by theory, the inventors have identified a newclass of cyclopropanamine-based LSD1 inhibitors with unexpected potencyand selectivity for LSD1, a biologically relevant target in oncology andother diseases.

All publications and patent applications mentioned in the specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference. The merementioning of the publications and patent applications does notnecessarily constitute an admission that they are prior art to theinstant application.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be obvious that certain changes and modificationsmay be practiced within the scope of the appended claims.

The invention claimed is:
 1. A compound chosen fromN-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)-2-cyanobenzenesulfonamide, anoptically active stereoisomer thereof, and a salt or solvate thereof. 2.The compound of claim 1, wherein the compound is an optically activestereoisomer.
 3. The compound of claim 1, wherein the compound isN-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)-2-cyanobenzenesulfonamide or apharmaceutically acceptable salt or solvate thereof.
 4. The compound ofclaim 1, wherein the compound is a hydrochloride salt ofN-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)-2-cyanobenzenesulfonamide.
 5. Apharmaceutical composition comprising a compound chosen fromN-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)-2-cyanobenzenesulfonamide,an optically active stereoisomer thereof, and a pharmaceuticallyacceptable salt or solvate thereof, and a pharmaceutically acceptablecarrier.
 6. The pharmaceutical composition of claim 5, wherein thecompound is an optically active stereoisomer.
 7. The pharmaceuticalcomposition of claim 5, wherein the compound isN-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)-2-cyanobenzenesulfonamideor a pharmaceutically acceptable salt or solvate thereof.
 8. Thepharmaceutical composition of claim 5, wherein the compound is ahydrochloride salt ofN-(4′-((trans)-2-((4-aminocyclohexyl)amino)cyclopropyl)-[1,1′-biphenyl]-3-yl)-2-cyanobenzenesulfonamide.